rs1673044

Positions:

• chr19-50403041-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Scores: Splicing: ADA: 0.00003048
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• 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]

ACMG classification

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: 5001 AN: 152162 Hom.: 272 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00814 AC: 1281 AN: 157454 Hom.: 64 AF XY: 0.00589 AC XY: 492 AN XY: 83486

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000330

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00325 AC: 4555 AN: 1401768 Hom.: 234 Cov.: 32 AF XY: 0.00280 AC XY: 1940 AN XY: 691834

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00853

Gnomad4 ASJ exome AF: 0.0000794

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000214

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.00766

GnomAD4 genome AF: 0.0330 AC: 5018 AN: 152280 Hom.: 274 Cov.: 33 AF XY: 0.0318 AC XY: 2371 AN XY: 74470

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0170 Hom.: 14

Bravo AF: 0.0381

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.93
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs1673044; hg19: chr19-50906298;