rs180177329
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152564.5(VPS13B):c.9185dupT(p.Leu3062fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
VPS13B
NM_152564.5 frameshift, splice_region
NM_152564.5 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.210
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 8-99823831-G-GT is Pathogenic according to our data. Variant chr8-99823831-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 2826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VPS13B | NM_017890.5 | c.9260dupT | p.Leu3087fs | frameshift_variant, splice_region_variant | 51/62 | ENST00000358544.7 | NP_060360.3 | |
| VPS13B | NM_152564.5 | c.9185dupT | p.Leu3062fs | frameshift_variant, splice_region_variant | 51/62 | ENST00000357162.7 | NP_689777.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VPS13B | ENST00000358544.7 | c.9260dupT | p.Leu3087fs | frameshift_variant, splice_region_variant | 51/62 | 1 | NM_017890.5 | ENSP00000351346.2 | ||
| VPS13B | ENST00000357162.7 | c.9185dupT | p.Leu3062fs | frameshift_variant, splice_region_variant | 51/62 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460936Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726824
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:5Other:1
| Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Leu3087Phefs*20) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15211651). It has also been observed to segregate with disease in related individuals. This variant is also known as c.9258_9259insT. ClinVar contains an entry for this variant (Variation ID: 2826). 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous p.Leu3087PhefsTer20 variant in VPS13B was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 845268), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 845268). The p.Leu3087PhefsTer20 variant in VPS13B has been previously reported in 2 unrelated individuals with Cohen syndrome and segregated with disease in 8 affected relatives from 2 families (PMID: 15211651). These previously reported individuals were homozygotes (PMID: 15211651), which increases the likelihood that the p.Leu3087PhefsTer20 variant is pathogenic. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 2826) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3087 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the VPS13B gene is an established disease mechanism in autosomal recessive Cohen syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3, PP1_Strong (Richards 2015). - |
not provided Pathogenic:1Other:1
| not provided, no classification provided | literature only | SNPedia | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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; This variant is associated with the following publications: (PMID: 29985682, 15211651, 20301655, 20461111, 16648375, 15141358) - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 15, 2020 | The c.9260dupT (p.L3087Ffs*20) alteration, located in exon 51 (coding exon 50) of the VPS13B gene, results from a duplication of one nucleotide at position 9260, causing a translational frameshift with a predicted alternate stop codon after 20 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in 8 affected children from an Amish kindred who were homozygous for this alteration (referred to as c.9258_9259dupT); their phenotypes included childhood-onset pigmentary retinopathy, progressive high myopia, global developmental delay, short stature, microcephaly, truncal hypotonia, joint hyperextensibility, small/narrow hands and feet, and dysmorphic facial features (Falk, 2004). Based on the available evidence, this alteration is classified as pathogenic. - |
VPS13B-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 26, 2024 | The VPS13B c.9185dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu3062Phefs*20). This variant has been reported in the homozygous state and along with another homozygous missense variant (c.8384T>C) in multiple individuals with Cohen syndrome from the Ohio Geauga Amish community (reported as c.9258_9259insT, Falk et al. 2004. PubMed ID: 15211651; reported as 9258insT in Table 1, Taban et al. 2007. PubMed ID: 17383910; Li et al. 2018. PubMed ID: 29985682). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been consistently classified as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/2826/). Frameshift variants in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at