rs892295785
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002691.4(POLD1):āc.3062A>Cā(p.His1021Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000586 in 1,534,974 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. H1021H) has been classified as Likely benign.
Frequency
Consequence
NM_002691.4 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3062A>C | p.His1021Pro | missense_variant | 24/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3062A>C | p.His1021Pro | missense_variant | 24/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000506 AC: 7AN: 1382854Hom.: 0 Cov.: 34 AF XY: 0.00000733 AC XY: 5AN XY: 682496
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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) - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1021 of the POLD1 protein (p.His1021Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 408028). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 26, 2022 | The p.H1021P variant (also known as c.3062A>C), located in coding exon 23 of the POLD1 gene, results from an A to C substitution at nucleotide position 3062. The histidine at codon 1021 is replaced by proline, 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