rs140160345
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_002691.4(POLD1):c.841-10A>G 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 0.0000477 in 1,572,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
POLD1
NM_002691.4 splice_polypyrimidine_tract, intron
NM_002691.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001221
2
Clinical Significance
Conservation
PhyloP100: -1.88
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 -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 19-50402602-A-G is Benign according to our data. Variant chr19-50402602-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 386416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.841-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.841-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000549 AC: 10AN: 182112Hom.: 0 AF XY: 0.0000411 AC XY: 4AN XY: 97420
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GnomAD4 exome AF: 0.0000486 AC: 69AN: 1419770Hom.: 0 Cov.: 34 AF XY: 0.0000441 AC XY: 31AN XY: 702480
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74512
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2018 | Variant summary: POLD1 c.841-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.3e-05 in 175902 control chromosomes. The observed variant frequency is approximately 4.4 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.841-10A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with two classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 22, 2017 | - - |
Carcinoma of colon Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 c.841-10A>G variant was not identified in the literature nor was it identified in the Cosmic or Clinvitae database. The variant was also identified in dbSNP (ID: rs140160345) as “With Likely benign allele”, ClinVar (classified as likely benign by GeneDx and Invitae; as uncertain significance by Quest Diagnostics Nichols Institute San Juan Capistrano), and LOVD 3.0 (1x) databases. The variant was identified in control databases in 11 of 175902 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 4280 chromosomes (freq: 0.0002), Latino in 1 of 25734 chromosomes (freq: 0.00004), European in 9 of 73424 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Colorectal cancer, susceptibility to, 10 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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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