rs201442356
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000553.6(WRN):c.2501G>A(p.Arg834His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,612,878 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R834C) has been classified as Likely benign.
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.2501G>A | p.Arg834His | missense_variant | 21/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.2501G>A | p.Arg834His | missense_variant | 21/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.1134G>A | non_coding_transcript_exon_variant | 9/23 | 1 | ||||
WRN | ENST00000520169.1 | n.340G>A | non_coding_transcript_exon_variant | 1/3 | 3 | ||||
WRN | ENST00000650667.1 | c.*2115G>A | 3_prime_UTR_variant, NMD_transcript_variant | 20/34 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151848Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251156Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135726
GnomAD4 exome AF: 0.0000240 AC: 35AN: 1460912Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 726740
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151966Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74282
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 834 of the WRN protein (p.Arg834His). This variant is present in population databases (rs201442356, gnomAD 0.03%). 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: 528176). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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