NM_002691.4:c.3054G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

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). Synonymous variant affecting the same amino acid position (i.e. V1018V) has been classified as Likely benign.

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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

POLD1-related polyposis and colorectal cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal cancer, susceptibility to, 10
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
mandibular hypoplasia-deafness-progeroid syndrome
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
Polymerase proofreading-related adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
immunodeficiency 120
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
non-severe combined immunodeficiency due to polymerase delta deficiency
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

POLD1 links:

ENSG00000142539 (HGNC:):

ENSG00000142539 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.068).

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 VariationId is 239329.

BP7

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

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

GnomAD2 exomes

AF:

0.000502

AC:

AN:

137366

AF XY:

0.000414

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 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

African (AFR)

AF:

0.000158

AC:

AN:

31558

American (AMR)

AF:

0.000726

AC:

AN:

35810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25138

East Asian (EAS)

AF:

0.00

AC:

AN:

35796

South Asian (SAS)

AF:

0.00

AC:

AN:

79218

European-Finnish (FIN)

AF:

0.00110

AC:

AN:

38338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4216

European-Non Finnish (NFE)

AF:

0.00135

AC:

1455

AN:

1079028

Other (OTH)

AF:

0.00100

AC:

AN:

57800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000972

AC:

148

AN:

152282

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41562

American (AMR)

AF:

0.00281

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

67992

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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) -

Apr 21, 2017

PreventionGenetics, part of Exact Sciences

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

- -

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. -

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

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLD1: BP4, BP7 -

Oct 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

May 08, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

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

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely 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

AlphaMissense

Benign

0.11

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.2

(source)

DANN

Benign

0.85

PhyloP100

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over