rs3218752

chr19-50416623-G-Achr19-50416623-G-Cchr19-50416623-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002691.4(POLD1):c.2967G>A(p.Thr989=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,563,834 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T989T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0029 (6 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -3.95

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-50416623-G-A is Benign according to our data. Variant chr19-50416623-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50416623-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.95 with no splicing effect.
• BS2: High AC in GnomAd at 213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2967G>A	p.Thr989=	synonymous_variant	24/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2967G>A	p.Thr989=	synonymous_variant	24/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152168 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000752

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00146 AC: 247 AN: 168900 Hom.: 0 AF XY: 0.00142 AC XY: 131 AN XY: 92250

Gnomad AFR exome AF: 0.000765

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00123

Gnomad FIN exome AF: 0.000512

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.00286 AC: 4033 AN: 1411548 Hom.: 6 Cov.: 34 AF XY: 0.00269 AC XY: 1880 AN XY: 698708

Gnomad4 AFR exome AF: 0.000527

Gnomad4 AMR exome AF: 0.000210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.000614

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152286 Hom.: 0 Cov.: 34 AF XY: 0.00132 AC XY: 98 AN XY: 74456

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000752

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLD1 p.Thr989Thr variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in dbSNP (ID: rs3218752 as “With Likely benign, other allele”), ClinVar (classified as benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano and as likely benign by GeneDx, Ambry Genetics and True Health Diagnostics), and Cosmic (1x in adenocarcinoma of the lung). The variant was identified in control databases in 275 of 194958 chromosomes at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 218 of 83548 chromosomes (freq: 0.003), African in 11 of 17348 chromosomes (freq: 0.0006), Other in 5 of 5074 chromosomes (freq: 0.001), Latino in 4 of 26990 chromosomes (freq: 0.0001), Finnish in 8 of 15338 chromosomes (freq: 0.0005), and South Asian in 29 of 24442 chromosomes (freq: 0.001), while it not observed in the Ashkenazi Jewish or East Asian populations. The p.Thr989= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	POLD1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2021	This variant is associated with the following publications: (PMID: 27923066) -

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 09, 2017	- -

Colorectal cancer, susceptibility to, 10 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 05, 2015	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.11
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3218752; hg19: chr19-50919880; COSMIC: COSV54532340; COSMIC: COSV54532340;