rs369613619

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_002691.4(POLD1):c.3054G>A(p.Val1018Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,539,184 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00097 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: -0.680

Variant links:

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]

POLD1 links:

ENSG00000142539 (HGNC:):

ENSG00000142539 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 19-50416710-G-A is Benign according to our data. Variant chr19-50416710-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239329.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=3, Uncertain_significance=1}. Variant chr19-50416710-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.68 with no splicing effect.

BS2

High AC in GnomAd4 at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.3054G>A	p.Val1018Val	synonymous_variant	Exon 24 of 27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.3054G>A	p.Val1018Val	synonymous_variant	Exon 24 of 27	1	NM_002691.4	ENSP00000406046.1		P28340
ENSG00000142539	ENST00000599632.1 link	c.261G>A	p.Val87Val	synonymous_variant	Exon 3 of 10	5		ENSP00000473233.1		M0R3H8

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000502

AC:

AN:

137366

Hom.:

AF XY:

0.000414

AC XY:

AN XY:

74800

show subpopulations

Gnomad AFR exome

AF:

0.000143

Gnomad AMR exome

AF:

0.000735

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000129

Gnomad NFE exome

AF:

0.000913

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.00114

AC:

1586

AN:

1386902

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

738

AN XY:

684676

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000726

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.00135

Gnomad4 OTH exome

AF:

0.00100

GnomAD4 genome

AF:

0.000972

AC:

148

AN:

152282

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000803

Hom.:

Bravo

AF:

0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

May 23, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The POLD1 c.3054G>A (p.Val1018Val) variant involves the alteration of a non-conserved nucleotide causes a synonymous change and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 89/139890 control chromosomes at a frequency of 0.0006362, which is approximately 45 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as Benign. -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLD1: BP4, BP7 -

Jun 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25356899) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10

Benign:2

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 23, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 03, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Polymerase proofreading-related adenomatous polyposis

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 p.Val1018= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs369613619) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, and ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by Invitae and 2 other laboratories, likely benign by GeneDx, Ambry Genetics, Prevention Genetics and 2 other laboratories, and uncertain significance by EGL Genetic Diagnostics (Eurofins Clinical Genetics)).The variant was identified in control databases in 89 of 162606 chromosomes at a frequency of 0.0005 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: African in 3 of 15192 chromosomes (freq: 0.0002), Other in 2 of 4524 chromosomes (freq: 0.0004), Latino in 17 of 24616 chromosomes (freq: 0.0007), European Non-Finnish in 63 of 64570 chromosomes (freq: 0.001), European Finnish in 4 of 11144 chromosomes (freq: 0.0004), while not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The variant was also identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic ATM variant (c.8418+5_8418+8del, r.spl?), increasing the likelihood the variant has little clinical significance. The p.Val1018= 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

-0.69

CADD

Benign

2.2

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over