rs780749621
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_002691.4(POLD1):c.3148C>T(p.Arg1050Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,606,422 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. R1050H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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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.3148C>T | p.Arg1050Cys | missense_variant | 26/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3148C>T | p.Arg1050Cys | missense_variant | 26/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000127 AC: 3AN: 236694Hom.: 0 AF XY: 0.0000232 AC XY: 3AN XY: 129116
GnomAD4 exome AF: 0.00000550 AC: 8AN: 1454146Hom.: 0 Cov.: 33 AF XY: 0.00000553 AC XY: 4AN XY: 723132
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152276Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74454
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1050 of the POLD1 protein (p.Arg1050Cys). 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: 537068). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | This sequence change replaces arginine with cysteine at codon 1050 of the POLD1 protein (p.Arg1050Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not found in gnomAD genomes. This variant has not been reported in the literature in individuals with POLD1-related disease. In-silico predictions show pathogenic computational verdict based on 9 pathogenic predictions from PolyPhen, DANN, DEOGEN2, FATHMM-MKL, LIST-S2, M-CAP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 3 benign predictions from BayesDel_addAF, EIGEN and MVP and it weakly conserved . Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The p.R1050C variant (also known as c.3148C>T), located in coding exon 25 of the POLD1 gene, results from a C to T substitution at nucleotide position 3148. The arginine at codon 1050 is replaced by cysteine, an amino acid with highly dissimilar 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