NM_002691.4:c.1646G>A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002691.4(POLD1):c.1646G>A(p.Arg549His) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,612,794 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R549C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1646G>A | p.Arg549His | missense_variant | Exon 13 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248960Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134778
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460636Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726618
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
POLD1-related disorder Uncertain:1
The POLD1 c.1646G>A variant is predicted to result in the amino acid substitution p.Arg549His. This variant has been reported in one individual with colorectal cancer (Table S3, Buchanan et al. 2018. PubMed ID: 29120461) and in at least one individual with dyslipidemia (Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50910391-G-A). This variant has been classified as a variant of uncertain significance in Clinvar by two different submitters (Clinvar ID: 239247). This variant is not located in the exonuclease domain of the POLD1 protein. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (Buchanan et al., 2017); This variant is associated with the following publications: (PMID: 29120461, 35620275, 32041611) -
Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 549 of the POLD1 protein (p.Arg549His). This variant is present in population databases (rs201038430, gnomAD 0.006%). 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: 239247). 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 expected to disrupt POLD1 protein function with a positive 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 Uncertain:1
The p.R549H variant (also known as c.1646G>A), located in coding exon 12 of the POLD1 gene, results from a G to A substitution at nucleotide position 1646. The arginine at codon 549 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at