rs3219457
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_002691.4(POLD1):c.3257G>A(p.Arg1086Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,610,986 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1086L) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 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 | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3257G>A | p.Arg1086Gln | missense_variant | 27/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3257G>A | p.Arg1086Gln | missense_variant | 27/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152038Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000827 AC: 20AN: 241976Hom.: 0 AF XY: 0.0000608 AC XY: 8AN XY: 131574
GnomAD4 exome AF: 0.0000459 AC: 67AN: 1458834Hom.: 1 Cov.: 31 AF XY: 0.0000482 AC XY: 35AN XY: 725404
GnomAD4 genome AF: 0.000243 AC: 37AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74390
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2018 | Variant summary: The POLD1 c.3257G>A (p.Arg1086Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 25/268244 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000871 (20/22966). This frequency is about 61 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is possibly a benign polymorphism found primarily in the populations of African origin. This population frequency data need to be considered with caution, since POLD1 pseudogenes have been reported. Two clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32041611, 20951805, 29717118, 19966286, 35620275, 12376507) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 08, 2021 | - - |
Colorectal cancer, susceptibility to, 10 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at