ClinVar Genomic variation as it relates to human health
NM_001128126.3(AP4S1):c.138+3_138+6del
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_001128126.3(AP4S1):c.138+3_138+6del
Variation ID: 234925 Accession: VCV000234925.32
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 14q12 14: 31066333-31066336 (GRCh38) [ NCBI UCSC ] 14: 31535539-31535542 (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 May 29, 2016 May 12, 2024 Aug 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001128126.3:c.138+3_138+6del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001128126.3:c.138+3_138+6delAAGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001254726.2:c.138+3_138+6del splice donor NM_001254727.2:c.138+3_138+6del splice donor NM_001254728.2:c.138+3_138+6del splice donor NM_001254729.2:c.138+3_138+6del splice donor NM_007077.3:c.138+3_138+6delAAGT NM_007077.5:c.138+3_138+6del splice donor NC_000014.9:g.31066333AAGT[1] NC_000014.8:g.31535539AAGT[1] NG_031913.1:g.46228AAGT[1] NG_031913.1:g.46232_46235del - Protein change
- Other names
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- Canonical SPDI
- NC_000014.9:31066332:AAGTAAGT:AAGT
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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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- Comment on variant
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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AP4S1 | - | - |
GRCh38 GRCh37 |
130 | 163 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2022 | RCV000223669.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2020 | RCV001260894.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 24, 2023 | RCV001268543.23 | |
APS41-related disorder
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not provided (1) |
no classification provided
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- | RCV001249231.9 |
Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2021 | RCV001374915.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 5, 2023 | RCV002516210.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 15, 2021 | RCV002516211.9 |
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
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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 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
unknown
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001437994.1
First in ClinVar: Oct 20, 2020 Last updated: Oct 20, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447535.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Hypotonia (present) , Spasticity (present)
Sex: male
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Pathogenic
(Feb 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001572202.1
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
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Pathogenic
(Mar 24, 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: SCV001764657.2
First in ClinVar: Aug 07, 2021 Last updated: Apr 15, 2023 |
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function as mRNA levels were virtually absent in the samples from affected individuals homozygous for c.1383_138+6delAAGT (Tessa … (more)
Non-canonical splice site variant demonstrated to result in loss-of-function as mRNA levels were virtually absent in the samples from affected individuals homozygous for c.1383_138+6delAAGT (Tessa et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31915823, 30293248, 27444738, 28150420, 25552650, 30552426) (less)
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Pathogenic
(Oct 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 52, autosomal recessive
Affected status: yes
Allele origin:
germline
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001994805.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
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Pathogenic
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063122.15
First in ClinVar: Jan 29, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 52, autosomal recessive
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680142.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Sex: female
Tissue: blood
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Pathogenic
(Jan 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 52, autosomal recessive
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577550.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM2, PP3, PP5
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Pathogenic
(Jan 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 52, autosomal recessive
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801542.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003277175.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 2 of the AP4S1 gene. It does not directly change the encoded amino acid sequence of the AP4S1 protein. … (more)
This sequence change falls in intron 2 of the AP4S1 gene. It does not directly change the encoded amino acid sequence of the AP4S1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs758873371, gnomAD 0.004%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 234925). This variant is also known as c.137_140delAAGT. This variant has been observed in individual(s) with AP4S1-related conditions (PMID: 25552650, 27444738, 28150420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. (less)
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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003559744.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.138+3_138+6delAAGT intronic variant, also known as c.137_140delAAGT, is located 3 nucleotides after coding exon 1 in the AP4S1 gene. This variant results from a … (more)
The c.138+3_138+6delAAGT intronic variant, also known as c.137_140delAAGT, is located 3 nucleotides after coding exon 1 in the AP4S1 gene. This variant results from a deletion of 4 nucleotides at positions c.138+3 to c.138+6. The stop codon in the predicted resulting transcript occurs in the 5' end of the AP4S1 gene. As such, this alteration may escape nonsense-mediated mRNA decay and/or be prone to rescue by reinitation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the AP4S1 c.138+3_138+6delAAGT alteration was observed in <0.01% (4/251148) of total alleles studied, with a frequency of <0.01% (4/113592) in the European (non-Finnish) subpopulation. This variant was detected as homozygous and compound heterozygous in multiple individuals with spastic paraplegia, intellectual disability, early-onset seizures, and other neurological findings consistent with AP4S1-related spastic parapelgia (Hardies, 2015; Tessa, 2016; Vill, 2017; Papuc, 2019). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jun 21, 2018)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 52, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000280014.2
First in ClinVar: May 29, 2016 Last updated: Jun 25, 2018 |
Comment on evidence:
In 2 sisters, born of unrelated Caucasian parents, with autosomal recessive spastic paraplegia-52 (SPG52; 614067), Hardies et al. (2015) identified compound heterozygous mutations in the … (more)
In 2 sisters, born of unrelated Caucasian parents, with autosomal recessive spastic paraplegia-52 (SPG52; 614067), Hardies et al. (2015) identified compound heterozygous mutations in the AP4S1 gene: a 4-bp deletion (c.137_140delAAGT, NM_007077.4), resulting in a frameshift and premature termination (Gln46ProfsTer9), and a c.289C-T transition, resulting in an arg97-to-ter (R97X; 607243.0003) substitution. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations were filtered against the 1000 Genomes Project and Exome Variant Server databases and 30 in-house genomes. The R97X variant was found at a low frequency (0.015%) in the Exome Variant Server. Western blot analysis of cells derived from 1 sister showed absence of the AP4S1 protein and a substantial reduction in all other AP4 subunits compared to controls. Immunoprecipitation studies confirmed the reduction of AP4 subunits and also showed impaired assembly of the complex. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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APS41-Related disorder
Affected status: yes
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV001423166.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormal delivery (present) , Short stature (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , … (more)
Abnormal delivery (present) , Short stature (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Seizures (present) , Abnormality of the curvature of the vertebral column (present) , Joint hypermobility (present) , Hip dysplasia (present) , Abnormality of facial musculature (present) , Abnormality of muscle physiology (present) , Abnormality of esophagus morphology (present) , Gingivitis (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-04-16
Testing laboratory interpretation: Pathogenic
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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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The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study. | Papuc SM | European journal of human genetics : EJHG | 2019 | PMID: 30552426 |
Allelic imbalance of somatic mutations in cancer genomes and transcriptomes. | Rhee JK | Scientific reports | 2017 | PMID: 28490743 |
A homozygous splice variant in AP4S1 mimicking neurodegeneration with brain iron accumulation. | Vill K | Movement disorders : official journal of the Movement Disorder Society | 2017 | PMID: 28150420 |
The rules and impact of nonsense-mediated mRNA decay in human cancers. | Lindeboom RG | Nature genetics | 2016 | PMID: 27618451 |
Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families. | Tessa A | European journal of neurology | 2016 | PMID: 27444738 |
Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome. | Rivas MA | Science (New York, N.Y.) | 2015 | PMID: 25954003 |
Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. | Hardies K | Human molecular genetics | 2015 | PMID: 25552650 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs876661295 ...
HelpRecord last updated May 19, 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.
NCBI staff reviewed the sequence in Figure 1 of the paper by Hardies et al., PubMed 25552650, to determine the location of the deletion.