chr8-31141440-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000553.6(WRN):c.2978G>A(p.Arg993His) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,613,870 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R993C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.2978G>A | p.Arg993His | missense_variant | 25/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.2978G>A | p.Arg993His | missense_variant | 25/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.1611G>A | non_coding_transcript_exon_variant | 13/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*2592G>A | 3_prime_UTR_variant, NMD_transcript_variant | 24/34 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152018Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251418Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461852Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727226
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152018Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74226
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 21, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 993 of the WRN protein (p.Arg993His). This variant is present in population databases (rs370713742, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 135427). 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: "Probably Damaging"; 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. - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at