rs778972543
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002691.4(POLD1):c.2464G>A(p.Asp822Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 1,608,798 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 (★★).
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.2464G>A | p.Asp822Asn | missense_variant | Exon 20 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248054Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134212
GnomAD4 exome AF: 0.00000412 AC: 6AN: 1456586Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4AN XY: 724304
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 822 of the POLD1 protein (p.Asp822Asn). This variant is present in population databases (rs778972543, 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: 408066). 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 Uncertain:1
The p.D822N variant (also known as c.2464G>A), located in coding exon 19 of the POLD1 gene, results from a G to A substitution at nucleotide position 2464. The aspartic acid at codon 822 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. 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 this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at