rs2230245
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_002691.4(POLD1):c.1485C>T(p.Thr495Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,580,166 control chromosomes in the GnomAD database, including 11,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.099 ( 966 hom., cov: 32)
Exomes 𝑓: 0.12 ( 10929 hom. )
Consequence
POLD1
NM_002691.4 synonymous
NM_002691.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -5.27
Genes affected
POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 19-50406508-C-T is Benign according to our data. Variant chr19-50406508-C-T is described in ClinVar as [Benign]. Clinvar id is 258787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50406508-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-5.27 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1485C>T | p.Thr495Thr | synonymous_variant | 12/27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1485C>T | p.Thr495Thr | synonymous_variant | 12/27 | 1 | NM_002691.4 | ENSP00000406046.1 |
Frequencies
GnomAD3 genomes AF: 0.0987 AC: 15005AN: 152050Hom.: 964 Cov.: 32
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GnomAD3 exomes AF: 0.105 AC: 20740AN: 198334Hom.: 1366 AF XY: 0.109 AC XY: 11565AN XY: 106122
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GnomAD4 exome AF: 0.119 AC: 169994AN: 1427996Hom.: 10929 Cov.: 35 AF XY: 0.120 AC XY: 84765AN XY: 707616
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GnomAD4 genome AF: 0.0987 AC: 15013AN: 152170Hom.: 966 Cov.: 32 AF XY: 0.100 AC XY: 7449AN XY: 74374
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 25, 2016 | Variant summary: The c.1485C>T (p.Thr495=) in POLD1 gene is a synonymous change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant may affect the normal splicing pattern by weakening the neighboring donor site, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.124 (5844/47134 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant of interest has not, to our knowledge, been reported in publications or cited by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Colorectal cancer, susceptibility to, 10 Benign:2
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Mandibular hypoplasia-deafness-progeroid syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Oct 25, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at