rs148269473
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006231.4(POLE):c.122C>T(p.Thr41Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T41K) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.122C>T | p.Thr41Met | missense_variant | 2/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.122C>T | p.Thr41Met | missense_variant | 2/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251468Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135912
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727240
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74432
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 41 of the POLE protein (p.Thr41Met). This variant is present in population databases (rs148269473, gnomAD 0.04%). 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: 405900). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | 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 - |
POLE-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2024 | The POLE c.122C>T variant is predicted to result in the amino acid substitution p.Thr41Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.035% of alleles in individuals of East Asian descent in gnomAD and it is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405900/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at