8-99481743-A-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_152564.5(VPS13B):c.3811A>T(p.Thr1271Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,613,984 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_152564.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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VPS13B | ENST00000358544.7 | c.3811A>T | p.Thr1271Ser | missense_variant | Exon 25 of 62 | 1 | NM_017890.5 | ENSP00000351346.2 | ||
VPS13B | ENST00000357162.7 | c.3811A>T | p.Thr1271Ser | missense_variant | Exon 25 of 62 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes AF: 0.000670 AC: 102AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000733 AC: 184AN: 251114Hom.: 0 AF XY: 0.000707 AC XY: 96AN XY: 135696
GnomAD4 exome AF: 0.000825 AC: 1206AN: 1461702Hom.: 2 Cov.: 31 AF XY: 0.000789 AC XY: 574AN XY: 727160
GnomAD4 genome AF: 0.000670 AC: 102AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:2
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VPS13B: BS2 -
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This variant is associated with the following publications: (PMID: 30792901) -
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
Cohen syndrome Uncertain:2Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Uncertain:2
Variant summary: VPS13B c.3811A>T (p.Thr1271Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 251114 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00073 vs 0.0025), allowing no conclusion about variant significance. c.3811A>T has been reported in the literature as a non-informative genotype in at-least one individual with a presumed diagnosis of Cohen syndrome who underwent a trio based whole genome sequencing (WGS) analysis (example, Scocchia_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=5; Likely Benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at