rs765998879
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.4238T>A(p.Leu1413Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,614,002 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
VPS13B
NM_017890.5 stop_gained
NM_017890.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.92
Genes affected
VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-99507850-T-A is Pathogenic according to our data. Variant chr8-99507850-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.4238T>A | p.Leu1413Ter | stop_gained | 28/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.4224+647T>A | intron_variant | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.4238T>A | p.Leu1413Ter | stop_gained | 28/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.4224+647T>A | intron_variant | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251332Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461808Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727212
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Leu1413*) 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 (rs765998879, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 371573). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2022 | Variant summary: VPS13B c.4238T>A (p.Leu1413X) 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 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 1.2e-05 in 251332 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4238T>A in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 20, 2016 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2022 | 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 a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;D;D
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at