8-99832368-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_152564.5(VPS13B):c.9331-1G>T variant causes a splice acceptor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_152564.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.9406-1G>T | splice_acceptor_variant, intron_variant | Intron 51 of 61 | ENST00000358544.7 | NP_060360.3 | ||
VPS13B | NM_152564.5 | c.9331-1G>T | splice_acceptor_variant, intron_variant | Intron 51 of 61 | ENST00000357162.7 | NP_689777.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.9406-1G>T | splice_acceptor_variant, intron_variant | Intron 51 of 61 | 1 | NM_017890.5 | ENSP00000351346.2 | |||
VPS13B | ENST00000357162.7 | c.9331-1G>T | splice_acceptor_variant, intron_variant | Intron 51 of 61 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 5468AN: 67484Hom.: 0 Cov.: 12 FAILED QC
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.111 AC: 64728AN: 583638Hom.: 1 Cov.: 32 AF XY: 0.108 AC XY: 31009AN XY: 288102
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0810 AC: 5467AN: 67510Hom.: 0 Cov.: 12 AF XY: 0.0771 AC XY: 2437AN XY: 31612
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:5
Variant summary: VPS13B c.9406-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Two predict the variant strengthens a cryptic 3 acceptor site in exon 52. These predictions were confirmed by at least one publication reporting experimental evidence that this variant affects mRNA splicing. Results showed that the variant lead to the deletion of 16 exonic bases and, thus, a frameshift in mRNA (Hennies 2004). The variant allele was not found in 57574 control chromosomes (gnomAD). c.9406-1G>T has been reported in the literature in multiple individuals affected with Cohen Syndrome in either homozygous or compound heterozygous state (Hennies 2004, Rauch 2006, Duplomb 2014) . These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a deficiency in Golgi N-glycosylation (Duplomb 2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change affects an acceptor splice site in intron 51 of the VPS13B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cohen syndrome (PMID: 15154116, 19190672). ClinVar contains an entry for this variant (Variation ID: 56699). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15154116). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
Observed in apparent homozygous state in patients with Cohen syndrome in the literature (Hennies 2004, Rauch 2006) and not observed in homozygous state in controls; Observed with another canonical splice variant in VPS13B, phase (cis or trans) unknown, in a patient with a personal history consistent with Cohen syndrome (El Chehadeh-Djebbar 2013); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25060287, 19190672, 15154116, 24334764, 16917849, 31825161, 31589614, 29618732, 23188044) -
VPS13B-related disorder Pathogenic:1
The VPS13B c.9331-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported as causative for autosomal recessive Cohen syndrome (described as c.9406-1G>T, Hennies et al. 2004. PubMed ID: 15154116; described as IVS51-1G>T, El Chehadeh-Djebbar et al. 2012. PubMed ID: 23188044; Duplomb et al. 2013. PubMed ID: 24334764). Variants that disrupt the consensus splice acceptor site in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at