rs180177360
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.4923G>A(p.Trp1641Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017890.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.4923G>A | p.Trp1641Ter | stop_gained | 31/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.4848G>A | p.Trp1616Ter | stop_gained | 31/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.4923G>A | p.Trp1641Ter | stop_gained | 31/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.4848G>A | p.Trp1616Ter | stop_gained | 31/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2022 | Observed along with a second nonsense variant in the VPS13B gene in multiple patients from one family with Cohen syndrome; however, segregation information was not provided (Seifert et al., 2006); Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21865173, 20461111, 15141358, 16648375) - |
Cohen syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 28, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 68086). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 16648375). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1641*) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at