19-50402620-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_002691.4(POLD1):c.849G>T(p.Gln283His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,573,394 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 22 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 18 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.976

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 19-50402620-G-T is Benign according to our data. Variant chr19-50402620-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 220697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50402620-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1532/152378) while in subpopulation AFR AF= 0.0349 (1453/41592). AF 95% confidence interval is 0.0334. There are 22 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1532 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.849G>T	p.Gln283His	missense_variant	Exon 8 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.849G>T	p.Gln283His	missense_variant	Exon 8 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.00994

AC:

1514

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0346

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00267

AC:

499

AN:

187218

Hom.:

AF XY:

0.00214

AC XY:

215

AN XY:

100482

show subpopulations

Gnomad AFR exome

AF:

0.0380

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000760

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000995

AC:

1414

AN:

1421016

Hom.:

Cov.:

AF XY:

0.000878

AC XY:

617

AN XY:

702946

show subpopulations

Gnomad4 AFR exome

AF:

0.0357

Gnomad4 AMR exome

AF:

0.00229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000852

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000275

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.0101

AC:

1532

AN:

152378

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

758

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0349

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00191

Hom.:

Bravo

AF:

0.0116

ESP6500AA

AF:

0.0324

AC:

142

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00252

AC:

303

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2016

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2016

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.849G>T (p.Gln283His) variant involves the alteration of a non-conserved nucleotide located at ribonuclease H-like domain of the protein (InterPro). 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 197/33948 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.048913 (189/3864). This frequency is about 3443 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a common benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -

May 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26249178) -

Hereditary cancer-predisposing syndrome

Benign:3

Nov 14, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 20, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_001308632.1(POLD1):c.849G>T (p.Gln283His) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 220697 as of 2025-01-02). There is a small physicochemical difference between glutamine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene POLD1 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.31. The gene POLD1 contains 8 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Benign -

May 21, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Polymerase proofreading-related adenomatous polyposis

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

POLD1, EXON8, c.849G>T, p.Gln283His, Heterozygous, BenignrnThe POLD1 p.Gln283His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs113282414) as "With other allele", and in ClinVar (classified as benign by Invitae, Counsyl, Ambry Genetics and four other submitters; as likely benign by two submitters). The variant was identified in control databases in 787 of 211816 chromosomes (15 homozygous) at a frequency of 0.004 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 713 of 18876 chromosomes (freq: 0.04), Other in 7 of 5358 chromosomes (freq: 0.001), Latino in 59 of 26974 chromosomes (freq: 0.002), European in 8 of 91128 chromosomes (freq: 0.00009); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln283 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 this variant meets our laboratory's criteria to be classified as benign.rnAssessment Date: 2019/05/24 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.12

T;.;.;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

.;.;T;T

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.0

N;.;.;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.75

N;.;.;.

REVEL

Benign

0.059

Sift

Benign

0.29

T;.;.;.

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.27

MutPred

0.42

Loss of ubiquitination at K280 (P = 0.1055);Loss of ubiquitination at K280 (P = 0.1055);Loss of ubiquitination at K280 (P = 0.1055);Loss of ubiquitination at K280 (P = 0.1055);

MVP

0.36

MPC

0.18

ClinPred

0.0037

GERP RS

2.1

Varity_R

0.094

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: 7

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