rs760077781
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_002691.4(POLD1):c.695G>A(p.Arg232His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,610,966 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232S) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.695G>A | p.Arg232His | missense_variant | 6/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.695G>A | p.Arg232His | missense_variant | 6/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152274Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246862Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133798
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1458692Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 725184
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74392
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 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 - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the POLD1 protein (p.Arg232His). This variant is present in population databases (rs760077781, gnomAD 0.007%). 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: 565934). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at