rs1057524200
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002691.4(POLD1):c.3118G>A(p.Glu1040Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000426 in 1,408,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002691.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3118G>A | p.Glu1040Lys | missense_variant, splice_region_variant | Exon 25 of 27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3118G>A | p.Glu1040Lys | missense_variant, splice_region_variant | Exon 25 of 27 | 1 | NM_002691.4 | ENSP00000406046.1 | ||
ENSG00000142539 | ENST00000599632.1 | c.325G>A | p.Glu109Lys | missense_variant, splice_region_variant | Exon 4 of 10 | 5 | ENSP00000473233.1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.00000594 AC: 1AN: 168210Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 89484
GnomAD4 exome AF: 0.00000426 AC: 6AN: 1408140Hom.: 0 Cov.: 33 AF XY: 0.00000431 AC XY: 3AN XY: 695630
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19296856, 27535533) -
Colorectal cancer, susceptibility to, 10 Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1040 of the POLD1 protein (p.Glu1040Lys). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 391703). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.E1040K variant (also known as c.3118G>A), located in coding exon 24 of the POLD1 gene, results from a G to A substitution at nucleotide position 3118. The glutamic acid at codon 1040 is replaced by lysine, an amino acid with 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