rs762090058
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006231.4(POLE):c.4139C>T(p.Ser1380Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S1380S) has been classified as Likely benign.
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.4139C>T | p.Ser1380Leu | missense_variant | 32/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.4139C>T | p.Ser1380Leu | missense_variant | 32/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250472Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135402
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460192Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 726112
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | 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: 473644). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (rs762090058, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1380 of the POLE protein (p.Ser1380Leu). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 20, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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: 29320758) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at