19-50402717-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002691.4(POLD1):c.946G>C(p.Asp316His) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,904 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_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.946G>C | p.Asp316His | missense_variant | Exon 8 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000409 AC: 1AN: 244464Hom.: 0 AF XY: 0.00000752 AC XY: 1AN XY: 132974
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1443904Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1AN XY: 714794
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 316 of the POLD1 protein (p.Asp316His). This variant is present in population databases (rs746087148, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 26133394). ClinVar contains an entry for this variant (Variation ID: 1409819). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLD1 function (PMID: 31750734). 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