ClinVar Genomic variation as it relates to human health
NM_001253852.3(AP4B1):c.1160_1161del (p.Thr387fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001253852.3(AP4B1):c.1160_1161del (p.Thr387fs)
Variation ID: 156414 Accession: VCV000156414.66
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 1p13.2 1: 113898755-113898756 (GRCh38) [ NCBI UCSC ] 1: 114441377-114441378 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2014 Apr 15, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001253852.3:c.1160_1161del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001240781.1:p.Thr387fs frameshift NM_001253852.2:c.1160_1161delCA NM_001253853.3:c.863_864del NP_001240782.1:p.Thr288fs frameshift NM_001308312.2:c.656_657del NP_001295241.1:p.Thr219fs frameshift NM_006594.3:c.1160_1161del NM_006594.5:c.1160_1161del NP_006585.2:p.Thr387fs frameshift NM_006594.5:c.1160_1161delCA NC_000001.11:g.113898756_113898757del NC_000001.10:g.114441378_114441379del NG_031901.1:g.11364_11365del - Protein change
- T219fs, T288fs, T387fs
- Other names
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- Canonical SPDI
- NC_000001.11:113898754:TGT:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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AP4B1 | - | - |
GRCh38 GRCh37 |
110 | 424 | |
AP4B1-AS1 | - | - | - | GRCh38 | - | 333 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000144484.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2016 | RCV000623767.5 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2023 | RCV001008108.24 | |
Likely benign (1) |
no assertion criteria provided
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Jan 1, 2019 | RCV001251672.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814068.4 | |
Likely pathogenic (1) |
no assertion criteria provided
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Oct 1, 2020 | RCV001849316.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 47
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369530.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP5. This variant was detected in homozygous state.
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 47
Affected status: yes
Allele origin:
unknown
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Paris Brain Institute, Inserm - ICM
Accession: SCV001451161.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 2
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755280.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Jan 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064319.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 47
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557266.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 47 (MIM#614066). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (37 heterozygotes, 0 homozygotes). (SP) 0701 - Many NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with spastic paraplegia 47 (ClinVar, PMID: 29193663). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(May 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 47
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580721.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Nov 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742035.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Autistic disorder of childhood onset (present) , Hypertonia (present) , Generalized hypotonia (present) , Nuchal cord (present) , Hypoglycemia (present) … (more)
Global developmental delay (present) , Autistic disorder of childhood onset (present) , Hypertonia (present) , Generalized hypotonia (present) , Nuchal cord (present) , Hypoglycemia (present) , Cephalohematoma (present) , Postnatal microcephaly (present) , Muscular hypotonia (present) , Shoulder dystocia (present) , Meconium stained amniotic fluid (present) (less)
Sex: male
Ethnicity/Population group: Asian/Ashkenazi Jewish
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 47
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004050663.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Nov 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001167858.2
First in ClinVar: Mar 16, 2020 Last updated: Nov 25, 2023 |
Comment:
Observed in homozygous state in several unrelated patients in published literature with hypotonia, spastic paraplegia, microcephaly, severe intellectual disability, and global developmental delay and not … (more)
Observed in homozygous state in several unrelated patients in published literature with hypotonia, spastic paraplegia, microcephaly, severe intellectual disability, and global developmental delay and not observed in homozygous state in controls (PMID: 32166732, 24781758); Reported with a second AP4B1 variant in an individual with SPG47 in the published literature (PMID: 29193663); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24781758, 21620353, 21440262, 22290197, 25552650, 25693842, 24700674, 19559397, 23167973, 20972249, 23472171, 31525725, 32166732, 31915823, 33728854, 32895917, 32964447, 33726816, 34544818, 34729478, 29193663) (less)
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Pathogenic
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 47
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000822690.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Thr387Argfs*30) in the AP4B1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Thr387Argfs*30) in the AP4B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4B1 are known to be pathogenic (PMID: 22290197, 24700674, 24781758). This variant is present in population databases (rs587779388, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with AP4B1-related conditions (PMID: 24781758). ClinVar contains an entry for this variant (Variation ID: 156414). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249619.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
AP4B1: PVS1, PM3:Strong, PM2
Number of individuals with the variant: 4
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: research
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spastic paraplegia 47, autosomal recessive; SPG47
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline
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Institute of Human Genetics, University Medical Center Hamburg-Eppendorf
Accession: SCV000119895.1
First in ClinVar: Oct 11, 2014 Last updated: Oct 11, 2014 |
Comment:
In two siblings who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia we detected the novel homozygous 2 bp deletion … (more)
In two siblings who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia we detected the novel homozygous 2 bp deletion c.1159_1160delCA in AP4B1; the mutation was present in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47 (SPG47). (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
severe ID (present) , absent speech (present) , microcephaly (present) , growth retardation (present) , progressive spastic tetraplegia (present)
Family history: yes
Age: 10-19 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: blood
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
severe ID (present) , absent speech (present) , microcephaly (present) , growth retardation (present) , progressive spastic tetraplegia (present)
Family history: yes
Age: 10-19 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: blood
Observation 3:
Number of individuals with the variant: 2
Clinical Features:
absence of severe ID (present) , absence of absent speech (present) , absence of microcephaly (present) , absence of growth retardation (present) , absence of … (more)
absence of severe ID (present) , absence of absent speech (present) , absence of microcephaly (present) , absence of growth retardation (present) , absence of progressive spastic tetraplegia (present) (less)
Family history: yes
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: blood
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Pathogenic
(Apr 30, 2014)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 47, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000256543.1
First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015 |
Comment on evidence:
In 2 sibs, born of unrelated parents, with autosomal recessive spastic paraplegia-47 (SPG47; 614066), Abdollahpour et al. (2015) identified a homozygous 2-bp deletion (c.1160_1161delCA, NM_006594.2) … (more)
In 2 sibs, born of unrelated parents, with autosomal recessive spastic paraplegia-47 (SPG47; 614066), Abdollahpour et al. (2015) identified a homozygous 2-bp deletion (c.1160_1161delCA, NM_006594.2) in exon 7 of the AP4B1 gene, resulting in a frameshift and premature termination (Thr387ArgfsTer30). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Although studies on patient cells and functional studies were not performed, the findings were consistent with a complete loss of protein function. (less)
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Likely benign
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
uniparental
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427412.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964319.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Likely pathogenic
(Oct 01, 2020)
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no assertion criteria provided
Method: literature only
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Spastic paraplegia
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106831.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953329.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. | Ebrahimi-Fakhari D | Brain : a journal of neurology | 2020 | PMID: 32979048 |
Clinical and genetic characterization of AP4B1-associated SPG47. | Ebrahimi-Fakhari D | American journal of medical genetics. Part A | 2018 | PMID: 29193663 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. | Abdollahpour H | European journal of human genetics : EJHG | 2015 | PMID: 24781758 |
Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. | Tüysüz B | American journal of medical genetics. Part A | 2014 | PMID: 24700674 |
Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) . | Bauer P | Neurogenetics | 2012 | PMID: 22290197 |
Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. | Abou Jamra R | American journal of human genetics | 2011 | PMID: 21620353 |
A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. | Blumkin L | Journal of the neurological sciences | 2011 | PMID: 21440262 |
Text-mined citations for rs587779388 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.