ClinVar Genomic variation as it relates to human health
NM_001160372.4(TRAPPC9):c.1414C>T (p.Arg472Ter)
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_001160372.4(TRAPPC9):c.1414C>T (p.Arg472Ter)
Variation ID: 759 Accession: VCV000000759.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.3 8: 140360131 (GRCh38) [ NCBI UCSC ] 8: 141370230 (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 Apr 4, 2013 May 1, 2024 Nov 8, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001160372.4:c.1414C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001153844.1:p.Arg472Ter nonsense NM_001321646.2:c.1387C>T NP_001308575.1:p.Arg463Ter nonsense NM_001374682.1:c.1435C>T NP_001361611.1:p.Arg479Ter nonsense NM_001374683.1:c.1414C>T NP_001361612.1:p.Arg472Ter nonsense NM_001374684.1:c.1351+10833C>T intron variant NM_031466.8:c.1414C>T NP_113654.5:p.Arg472Ter nonsense NR_164662.1:n.1503C>T non-coding transcript variant NC_000008.11:g.140360131G>A NC_000008.10:g.141370230G>A NG_016478.3:g.103449C>T LRG_1041:g.103449C>T LRG_1041t1:c.1414C>T LRG_1041p1:p.Arg472Ter LRG_1041t2:c.1414C>T LRG_1041p2:p.Arg472Ter - Protein change
- R472*, R463*, R479*
- Other names
- R570*
- Canonical SPDI
- NC_000008.11:140360130:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- absent gene product Sequence Ontology [SO:0002317]
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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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TRAPPC9 | - | - |
GRCh38 GRCh37 |
857 | 937 |
Conditions - Germline
Condition
Help
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
Help
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2021 | RCV000000795.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2021 | RCV000273297.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2021 | RCV002512619.2 |
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
(May 27, 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: SCV003711996.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1708C>T (p.R570*) alteration, located in exon 9 (coding exon 9) of the TRAPPC9 gene, consists of a C to T substitution at nucleotide position … (more)
The c.1708C>T (p.R570*) alteration, located in exon 9 (coding exon 9) of the TRAPPC9 gene, consists of a C to T substitution at nucleotide position 1708. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 570. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been identified as homozygous in three brothers from a consanguineous Tunisian family with autosomal recessive intellectual disability, mild microcephaly, and white matter abnormalities (Philippe, 2009). Expression studies showed an undetectable level of TRAPPC9 protein in patient skin fibroblasts (Philippe, 2009). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(Jan 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 13
Affected status: yes
Allele origin:
inherited
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965775.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Pathogenic
(Jun 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 13
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline
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Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax
Accession: SCV001749120.1
First in ClinVar: Jul 14, 2021 Last updated: Jul 14, 2021 |
Comment:
The p.Arg472Ter variant in the TRAPPC9 gene has been already reported in the homozygous state in two separately consanguineous Tunisian families of three siblings with … (more)
The p.Arg472Ter variant in the TRAPPC9 gene has been already reported in the homozygous state in two separately consanguineous Tunisian families of three siblings with autosomal recessive microcephaly and intellectual disability (Philippe et al., 2009 and Mortreux et al.,2018). In vitro studies of the p.Arg472Ter variant revealed undetectable levels of TRAPPC9 protein in skin fibroblasts from a patient with the homozygous p.Arg472Ter variant (Philippe et al., 2009). The p.Arg472Ter is a very rare variant, reported in heterozygous state in the gnomAD (exome) database with AF=0.0032 % ( 8 alleles of 251,490). We interpret the p.Arg472Ter as a pathogenic variant.(ACMG criteria : PVS1,PP5,PM2,PP3) (less)
Observation 1:
Clinical Features:
Intellectual disability, severe (present) , Primary microcephaly (present) , Seizure (present) , Autistic behavior (present) , Brain imaging abnormality (present) , Abnormal facial shape (present)
Family history: yes
Age: 0-9 years
Sex: male
Ethnicity/Population group: North Africa
Geographic origin: Tunisian
Tissue: Blood
Segregation observed: yes
Secondary finding: no
Method: TruSightâ„¢ One Sequencing Panel
Observation 2: Observation 3: Observation 4: Observation 5: Observation 6: |
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Pathogenic
(Nov 08, 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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GeneDx
Accession: SCV000329560.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense 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; Not … (more)
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22549410, 30272317, 20004764, 29187737, 30853973, 30152084, 29031008, 32434006, 34737153) (less)
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Pathogenic
(Dec 01, 2009)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 13
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020945.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment on evidence:
In 3 brothers, born of consanguineous Tunisian parents, with autosomal recessive intellectual developmental disorder-13 (MRT13; 613192), Philippe et al. (2009) identified a homozygous 1708C-T transition … (more)
In 3 brothers, born of consanguineous Tunisian parents, with autosomal recessive intellectual developmental disorder-13 (MRT13; 613192), Philippe et al. (2009) identified a homozygous 1708C-T transition in exon 9 of the TRAPPC9 gene, resulting in an arg570-to-ter (R570X) substitution. The mutation was not found in 1,120 control chromosomes. The protein was not detected in patient fibroblasts, and the authors postulated nonsense-mediated mRNA decay. In cultured patient fibroblasts, stimulation with TNF-alpha (191160) showed a defect in IKBA (NFKBIA; 164008) degradation, suggesting impaired function of the NF-kappa-B (see 164011) signaling pathway. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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absent gene product
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Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax
Accession: SCV001749120.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability. | Mortreux J | European journal of human genetics : EJHG | 2018 | PMID: 29187737 |
Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation. | Philippe O | American journal of human genetics | 2009 | PMID: 20004764 |
Text-mined citations for rs267607137 ...
HelpRecord last updated May 01, 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.