rs780775837
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_006231.4(POLE):c.449G>A(p.Arg150Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R150G) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.449G>A | p.Arg150Gln | missense_variant | 6/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.449G>A | p.Arg150Gln | missense_variant | 6/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251146Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135710
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1459440Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5AN XY: 725440
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 150 of the POLE protein (p.Arg150Gln). 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: 240522). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (rs780775837, gnomAD 0.006%). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2020 | 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2015 | <span style="font-size:12px">Thep.R150Qvariant (also known as c.449G>A), located in codingexon6 of thePOLEgene, results from a G to A substitution at nucleotide position 449. Thearginineatcodon150 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single NucleotidePolymorphisms(dbSNP),NHLBIExomeSequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. 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 p.R150Q remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at