rs386834055
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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.10081dupA(p.Thr3361fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
VPS13B
NM_152564.5 frameshift
NM_152564.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.26
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 8-99853469-T-TA is Pathogenic according to our data. Variant chr8-99853469-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VPS13B | ENST00000358544.7 | c.10156dupA | p.Thr3386fs | frameshift_variant | 56/62 | 1 | NM_017890.5 | ENSP00000351346.2 | ||
| VPS13B | ENST00000357162.7 | c.10081dupA | p.Thr3361fs | frameshift_variant | 56/62 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251138Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135800
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727240
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GnomAD4 genome 0.0000263 AC: 4AN: 152348Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74500
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Feb 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Thr3386Asnfs*3) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Cohen Syndrome (PMID: 22855652). ClinVar contains an entry for this variant (Variation ID: 56629). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 01, 2016 | This inherited recessive pathogenic mutation in the VPS13B gene in combination with a second recessive pathogenic mutation in the same gene, NM_152564.4:c.10165_10207del, was observed in a patient with Cohen syndrome. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 17, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | - | A homozygous single base pair duplication in exon 56 of the VPS13B gene that results in a frameshift and premature truncation of the protein 3 amino acids downstream to codon 3361 was detected. This variant has not been reported in the 1000 genomes databases. The reference region is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. - |
| Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift duplication p.T3386Nfs*3 in VPS13B (NM_017890.5) has previously been reported in the literature in individuals affected with Cohen Syndrome (Athanasakis_2012). The variant has been reported to ClinVar as Pathogenic/Likely Pathogenic. The p.T3386Nfs*3 variant is observed in 6/30,610 (0.0196%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The p.T3386Nfs*3 variant is a loss of function variant in the gene VPS13B, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NM_017890.5:c.292-1G>A and 155 others. 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 | Aug 12, 2019 | Variant summary: VPS13B c.10156dupA (p.Thr3386AsnfsX3) 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. The variant allele was found at a frequency of 3.6e-05 in 251338 control chromosomes. c.10156dupA has been reported in the literature in individuals affected with Cohen Syndrome (Athanasakis_2012) . These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 11, 2019 | The VPS13B c.10156dupA p.(Thr3386AsnfsTer3) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a splice region variant in an Italian individual with Cohen syndrome who exhibited psychomotor development, severe language impairment, hypotonia, joint laxity, neutropenia, exotropia, macular atrophy, and friendly behavior (Athanasakis et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000196 in the South Asian population (version 2.1.1). Based on the available evidence, the p.(Thr3386AsnfsTer3) variant is classified as pathogenic for Cohen syndrome. - |
not provided Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Nov 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2022 | 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: 22855652) - |
Computational scores
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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