12-132649756-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The ENST00000320574.10(POLE):āc.3716A>Gā(p.Gln1239Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1239L) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000320574.10 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.3716A>G | p.Gln1239Arg | missense_variant | 30/49 | ENST00000320574.10 | NP_006222.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.3716A>G | p.Gln1239Arg | missense_variant | 30/49 | 1 | NM_006231.4 | ENSP00000322570 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251422Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727246
GnomAD4 genome AF: 0.000138 AC: 21AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 17, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2023 | 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; This variant is associated with the following publications: (PMID: Shah2022[Preprint]) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1239 of the POLE protein (p.Gln1239Arg). This variant is present in population databases (rs146210785, gnomAD 0.03%). 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: 420338). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2021 | The c.3716A>G (p.Q1239R) alteration is located in exon 30 (coding exon 30) of the POLE gene. This alteration results from a A to G substitution at nucleotide position 3716, causing the glutamine (Q) at amino acid position 1239 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 23, 2021 | - - |
POLE-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 15, 2024 | The POLE c.3716A>G variant is predicted to result in the amino acid substitution p.Gln1239Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD, and it has conflicting interpretations in ClinVar including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/420338/). 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