rs120074152
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.2911C>T(p.Arg971Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017890.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.2911C>T | p.Arg971Ter | stop_gained | 20/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.2911C>T | p.Arg971Ter | stop_gained | 20/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.2911C>T | p.Arg971Ter | stop_gained | 20/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.2911C>T | p.Arg971Ter | stop_gained | 20/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251120Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135730
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461460Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727048
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74292
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg971*) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs120074152, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15154116). ClinVar contains an entry for this variant (Variation ID: 2823). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jan 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2021 | Variant summary: VPS13B c.2911C>T (p.Arg971X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251120 control chromosomes. c.2911C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Cohen Syndrome (e.g. Hennies_2004, Seifert_2008, Duplomb_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 12, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at