12-132638132-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_006231.4(POLE):c.5560G>A(p.Ala1854Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5560G>A | p.Ala1854Thr | missense_variant | Exon 41 of 49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5560G>A | p.Ala1854Thr | missense_variant | Exon 41 of 48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4639G>A | p.Ala1547Thr | missense_variant | Exon 33 of 40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2548G>A | p.Ala850Thr | missense_variant | Exon 17 of 24 | XP_011533104.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151914Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251194Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135788
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461346Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726994
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1854 of the POLE protein (p.Ala1854Thr). This variant is present in population databases (rs557167678, 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: 473741). 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 not expected to disrupt POLE protein function with a negative 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 does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at