rs1555301272
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_006231.4(POLE):āc.6344A>Gā(p.Asp2115Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Synonymous variant affecting the same amino acid position (i.e. D2115D) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6344A>G | p.Asp2115Gly | missense_variant | 46/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6344A>G | p.Asp2115Gly | missense_variant | 46/48 | ||
POLE | XM_011534797.4 | c.5423A>G | p.Asp1808Gly | missense_variant | 38/40 | ||
POLE | XM_011534802.4 | c.3332A>G | p.Asp1111Gly | missense_variant | 22/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6344A>G | p.Asp2115Gly | missense_variant | 46/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461336Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726964
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2115 of the POLE protein (p.Asp2115Gly). This variant has not been reported in the literature in individuals affected with POLE-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. ClinVar contains an entry for this variant (Variation ID: 473796). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at