rs771789997
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_002691.4(POLD1):c.2969G>A(p.Arg990His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,563,992 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. R990C) 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 Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2969G>A | p.Arg990His | missense_variant | 24/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2969G>A | p.Arg990His | missense_variant | 24/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000992 AC: 14AN: 1411796Hom.: 0 Cov.: 34 AF XY: 0.0000100 AC XY: 7AN XY: 698868
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
POLD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 09, 2023 | The POLD1 c.2969G>A variant is predicted to result in the amino acid substitution p.Arg990His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50919882-G-A). It is interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/537051/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 14, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 990 of the POLD1 protein (p.Arg990His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 537051). 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. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2023 | The p.R990H variant (also known as c.2969G>A), located in coding exon 23 of the POLD1 gene, results from a G to A substitution at nucleotide position 2969. The arginine at codon 990 is replaced by histidine, 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