rs267607007
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_000553.6(WRN):āc.373A>Gā(p.Lys125Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,542 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 (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K125N) 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 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.373A>G | p.Lys125Glu | missense_variant | 5/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.373A>G | p.Lys125Glu | missense_variant | 5/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000650667.1 | c.227A>G | p.Lys76Arg | missense_variant, NMD_transcript_variant | 4/34 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461314Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726974
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74382
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 156353). This variant has not been reported in the literature in individuals affected with WRN-related conditions. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 125 of the WRN protein (p.Lys125Glu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at