rs386834116
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_017890.5(VPS13B):c.8697-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
VPS13B
NM_017890.5 splice_polypyrimidine_tract, intron
NM_017890.5 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9865
2
Clinical Significance
Conservation
PhyloP100: 0.240
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 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 8-99819403-A-G is Pathogenic according to our data. Variant chr8-99819403-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99819403-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.8697-9A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000358544.7 | |||
VPS13B | NM_152564.5 | c.8622-9A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.8622-9A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_152564.5 | P1 | |||
VPS13B | ENST00000358544.7 | c.8697-9A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250926Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135698
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461226Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726914
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GnomAD4 genome ? Cov.: 32
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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
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 05, 2022 | This variant has been observed in individual(s) with Cohen syndrome (PMID: 22855652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs386834116, gnomAD 0.003%). This sequence change falls in intron 47 of the VPS13B gene. It does not directly change the encoded amino acid sequence of the VPS13B protein. ClinVar contains an entry for this variant (Variation ID: 56697). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 03, 2023 | Variant summary: VPS13B c.8697-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site eight nucleotides upstream into intron 47. Two predict the variant abolishes the canonical 3' acceptor site and one predicts the variant weakens the canonical 3' acceptor site. This impact on splicing was confirmed via cDNA sequencing by Athanasakis_2012. The variant allele was found at a frequency of 4e-06 in 250926 control chromosomes (gnomAD). c.8697-9A>G has been reported in the literature in at least one compound heterozygous individuals affected with Cohen Syndrome (Athanasakis_2012). These data do not allow any conclusion about variant significance. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2016 | The c.8697-9A>G variant in the VPS13B gene has been reported previously in an individual with Cohen syndrome who harbored this variant in trans with another pathogenic variant (Athanasakis et al., 2012). The c.8697-9A>G variant creates a cryptic splice acceptor site 8 base pairs upstream of the canonical splice acceptor site in intron 47. In vitro studies demonstrated that this variant results in an abnormal message and is predicted to lead to nonsense-mediated mRNA decay if the message is used for protein translation (Athanasakis et al., 2012). The c.8697-9A>G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.8697-9A>G as a pathogenic variant. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at