rs1673044
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_002691.4(POLD1):c.971-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,554,048 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.033 ( 274 hom., cov: 33)
Exomes 𝑓: 0.0032 ( 234 hom. )
Consequence
POLD1
NM_002691.4 splice_polypyrimidine_tract, intron
NM_002691.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00003048
2
Clinical Significance
Conservation
PhyloP100: 0.00500
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 19-50403041-C-T is Benign according to our data. Variant chr19-50403041-C-T is described in ClinVar as [Benign]. Clinvar id is 380635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403041-C-T is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.971-12C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.971-12C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0329 AC: 5001AN: 152162Hom.: 272 Cov.: 33
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GnomAD3 exomes AF: 0.00814 AC: 1281AN: 157454Hom.: 64 AF XY: 0.00589 AC XY: 492AN XY: 83486
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GnomAD4 exome AF: 0.00325 AC: 4555AN: 1401768Hom.: 234 Cov.: 32 AF XY: 0.00280 AC XY: 1940AN XY: 691834
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GnomAD4 genome ? AF: 0.0330 AC: 5018AN: 152280Hom.: 274 Cov.: 33 AF XY: 0.0318 AC XY: 2371AN XY: 74470
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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:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 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, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Colorectal cancer, susceptibility to, 10 Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 27, 2024 | This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 c.971-12C>T variant was identified in dbSNP (ID: rs1673044) “With Benign allele”, ClinVar (classified benign by GeneDx), and in control databases in 2164 (125 homozygous) of 181834 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1920 (124 homozygous) of 16668 chromosomes (freq: 0.12), Other in 23 of 4858 chromosomes (freq: 0.005), Latino in 194 (1 homozygous) of 25214 chromosomes (freq: 0.008), European Non-Finnish in 24 of 72526 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 8564 chromosomes (freq: 0.0001), and South Asian in 2 of 23094 chromosomes (freq: 0.00009), while not observed in the East Asian and European Finnish populations. The c.971-12C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing for c.971-12C>T. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 21, 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
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at