19-50414986-G-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002691.4(POLD1):c.2560G>T(p.Asp854Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,575,790 control chromosomes in the GnomAD database, including 1 homozygotes. 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_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2560G>T | p.Asp854Tyr | missense_variant | Exon 20 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000251 AC: 5AN: 199096Hom.: 0 AF XY: 0.0000462 AC XY: 5AN XY: 108242
GnomAD4 exome AF: 0.0000344 AC: 49AN: 1423618Hom.: 1 Cov.: 31 AF XY: 0.0000468 AC XY: 33AN XY: 705588
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:2
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not specified Uncertain:1
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Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 854 of the POLD1 protein (p.Asp854Tyr). This variant is present in population databases (rs373650022, gnomAD 0.005%). 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: 239300). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.D854Y variant (also known as c.2560G>T), located in coding exon 19 of the POLD1 gene, results from a G to T substitution at nucleotide position 2560. The aspartic acid at codon 854 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at