rs1060501820
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The ENST00000440232.7(POLD1):c.2574G>T(p.Glu858Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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. E858G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000440232.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2574G>T | p.Glu858Asp | missense_variant | 21/27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2574G>T | p.Glu858Asp | missense_variant | 21/27 | 1 | NM_002691.4 | ENSP00000406046 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1460244Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21AN XY: 726406
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | A heterozygous missense variant was identified, NM_001256849.1(POLD1):c.2574G>T in exon 21 of 27 of the POLD1 gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to an aspartic acid at position 858 of the protein; NP_001243778.1(POLD1):p.(Glu858Asp). The glutamic acid at this position has low conservation (100 vertebrates, UCSC), but is located within the polymerase active site region (Weedon, M. N. et al. (2013)). In silico software predicts this variant to be tolerated (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously been reported as a VUS (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 408005). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 858 of the POLD1 protein (p.Glu858Asp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at