rs1433696636
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_002691.4(POLD1):c.1223C>G(p.Ser408Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,674 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S408F) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1223C>G | p.Ser408Cys | missense_variant | 10/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1223C>G | p.Ser408Cys | missense_variant | 10/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460500Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 726666
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 05, 2021 | The p.S408C variant (also known as c.1223C>G), located in coding exon 9 of the POLD1 gene, results from a C to G substitution at nucleotide position 1223. The serine at codon 408 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 21, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 07, 2019 | - - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 408 of the POLD1 protein (p.Ser408Cys). 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: 469186). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at