rs756829894
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_006231.4(POLE):c.1480C>T(p.Arg494Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,138 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 (★★).
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248632Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134618
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461138Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726836
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 494 of the POLE protein (p.Arg494Trp). This variant is present in population databases (rs756829894, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 473461). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. 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 observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at