rs200736325
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_002691.4(POLD1):c.187G>A(p.Glu63Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,554,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.187G>A | p.Glu63Lys | missense_variant | 2/27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.187G>A | p.Glu63Lys | missense_variant | 2/27 | 1 | NM_002691.4 | ENSP00000406046.1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000682 AC: 11AN: 161302Hom.: 0 AF XY: 0.0000708 AC XY: 6AN XY: 84760
GnomAD4 exome AF: 0.0000257 AC: 36AN: 1402336Hom.: 0 Cov.: 33 AF XY: 0.0000246 AC XY: 17AN XY: 691956
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74506
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | POLD1: BP4 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 15, 2017 | - - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 63 of the POLD1 protein (p.Glu63Lys). This variant is present in population databases (rs200736325, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407981). 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 POLD1 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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at