chr12-132642606-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_006231.4(POLE):āc.4852A>Gā(p.Asn1618Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,440 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1618S) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.4852A>G | p.Asn1618Asp | missense_variant | 37/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.4852A>G | p.Asn1618Asp | missense_variant | 37/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251116Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135770
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461264Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726922
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2019 | 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 that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31034466, 29056344) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 405612). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (rs377406943, gnomAD 0.009%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1618 of the POLE protein (p.Asn1618Asp). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2024 | The p.N1618D variant (also known as c.4852A>G), located in coding exon 37 of the POLE gene, results from an A to G substitution at nucleotide position 4852. The asparagine at codon 1618 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at