8-31096770-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000553.6(WRN):c.1901G>A(p.Gly634Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000373 in 1,608,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. G634S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000553.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.1901G>A | p.Gly634Asp | missense_variant, splice_region_variant | 17/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.1901G>A | p.Gly634Asp | missense_variant, splice_region_variant | 17/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.534G>A | splice_region_variant, non_coding_transcript_exon_variant | 5/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*1515G>A | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 16/34 |
Frequencies
GnomAD3 genomes AF: 0.00000665 AC: 1AN: 150268Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000523 AC: 13AN: 248664Hom.: 0 AF XY: 0.0000520 AC XY: 7AN XY: 134568
GnomAD4 exome AF: 0.0000405 AC: 59AN: 1457782Hom.: 0 Cov.: 33 AF XY: 0.0000414 AC XY: 30AN XY: 725312
GnomAD4 genome AF: 0.00000665 AC: 1AN: 150268Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1AN XY: 73204
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The c.1901G>A (p.G634D) alteration is located in exon 17 (coding exon 16) of the WRN gene. This alteration results from a G to A substitution at nucleotide position 1901, causing the glycine (G) at amino acid position 634 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 634 of the WRN protein (p.Gly634Asp). This variant is present in population databases (rs759533715, 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: 404050). 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: "Possibly 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at