rs549125520
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_017890.5(VPS13B):c.10757G>A(p.Arg3586Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,613,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3586W) has been classified as Uncertain significance.
Frequency
Consequence
NM_017890.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.10757G>A | p.Arg3586Gln | missense_variant | 56/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.10682G>A | p.Arg3561Gln | missense_variant | 56/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.10757G>A | p.Arg3586Gln | missense_variant | 56/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.10682G>A | p.Arg3561Gln | missense_variant | 56/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251304Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135818
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461284Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 726810
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74392
ClinVar
Submissions by phenotype
Cohen syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 01, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3586 of the VPS13B protein (p.Arg3586Gln). This variant is present in population databases (rs549125520, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 528848). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
VPS13B-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2023 | The VPS13B c.10682G>A variant is predicted to result in the amino acid substitution p.Arg3561Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-100866299-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at