rs754985773
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000553.6(WRN):āc.2747A>Cā(p.His916Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,612,886 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 ā ).
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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152086Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 250990Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135742
GnomAD4 exome AF: 0.000118 AC: 173AN: 1460800Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81AN XY: 726674
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152086Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74308
ClinVar
Submissions by phenotype
not specified Uncertain:1
DNA sequence analysis of the WRN gene demonstrated a sequence change, c.2747A>C, in exon 23 that results in an amino acid change, p.His916Pro. This sequence change does not appear to have been previously described in patients with WRN-related disorders and has been described in the gnomAD database with a frequency of 0.02% in European populations (dbSNP rs754985773). The p.His916Pro change affects a highly conserved amino acid residue located in a domain of the WRN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His916Pro substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.His916Pro change remains unknown at this time. -
Werner syndrome Uncertain:1
This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 916 of the WRN protein (p.His916Pro). This variant is present in population databases (rs754985773, gnomAD 0.02%). 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: 404018). 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. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individual with dyslipidemia and/or a metabolic disorder in published literature (Dron et al., 2020); This variant is associated with the following publications: (PMID: 32041611) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at