rs538046428
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_002691.4(POLD1):āc.1032G>Cā(p.Trp344Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000256 in 1,564,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W344L) 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.1032G>C | p.Trp344Cys | missense_variant | 9/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1032G>C | p.Trp344Cys | missense_variant | 9/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000583 AC: 1AN: 171606Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 91438
GnomAD4 exome AF: 0.00000212 AC: 3AN: 1411886Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1AN XY: 697844
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152304Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74478
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | ClinVar contains an entry for this variant (Variation ID: 935880). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. 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 sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 344 of the POLD1 protein (p.Trp344Cys). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2019 | The p.W344C variant (also known as c.1032G>C), located in coding exon 8 of the POLD1 gene, results from a G to C substitution at nucleotide position 1032. The tryptophan at codon 344 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at