chr19-50417031-C-T

Variant names:

• chr19-50417031-C-T
• rs3218758
• NM_002691.4:c.3068-14C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002691.4(POLD1):​c.3068-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,548,128 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -1.51

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]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-50417031-C-T is Benign according to our data. Variant chr19-50417031-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 371996.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3068-14C>T		intron_variant	Intron 24 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3068-14C>T		intron_variant	Intron 24 of 26	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.275-14C>T		intron_variant	Intron 3 of 9	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000443 AC: 68 AN: 153528 Hom.: 0 AF XY: 0.000445 AC XY: 36 AN XY: 80966

Gnomad AFR exome AF: 0.000118

Gnomad AMR exome AF: 0.000244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.000206

Gnomad NFE exome AF: 0.000878

Gnomad OTH exome AF: 0.000695

GnomAD4 exome AF: 0.000631 AC: 881 AN: 1395806 Hom.: 0 Cov.: 33 AF XY: 0.000638 AC XY: 439 AN XY: 688276

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000253

Gnomad4 ASJ exome AF: 0.0000798

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.000758

Gnomad4 OTH exome AF: 0.000554

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152322 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74472

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.000408

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Benign:3

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Dec 19, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 25, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 03, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3068-14C>T intronic alteration consists of a C to T substitution 14 nucleotides before coding exon 24 in the POLD1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.3068-14C>T variant was not identified in the literature, nor was it identified in the COSMIC database. The variant was identified in dbSNP (ID: rs3218758) as "With Likely benign allele", ClinVar (classified as likely benign by Counsyl and GeneDx), and Clinvitae. The variant was identified in control databases in 76 of 177654 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 16356 chromosomes (freq: 0.0001), Other in 1 of 4758 chromosomes (freq: 0.0002), Latino in 7 of 24694 chromosomes (freq: 0.0003), European in 60 of 71074 chromosomes (freq: 0.001), Finnish in 4 of 17792 chromosomes (freq: 0.0002), and South Asian in 3 of 22678 chromosomes (freq: 0.0001); but not observed in the Ashkenazi Jewish, or East 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3218758; hg19: chr19-50920288;