rs141519273
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_006231.4(POLE):c.5515C>T(p.Arg1839Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,998 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
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5515C>T | p.Arg1839Cys | missense_variant | Exon 40 of 49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5515C>T | p.Arg1839Cys | missense_variant | Exon 40 of 48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4594C>T | p.Arg1532Cys | missense_variant | Exon 32 of 40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2503C>T | p.Arg835Cys | missense_variant | Exon 16 of 24 | XP_011533104.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251404Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727242
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:3
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1839 of the POLE protein (p.Arg1839Cys). This variant is present in population databases (rs141519273, gnomAD 0.01%). 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: 405582). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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 specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at