NM_002691.4:c.849G>T

Variant names:

• chr19-50402620-G-T
• rs113282414
• NM_002691.4:c.849G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q283R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.976
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.849G>T	p.Gln283His	missense_variant	Exon 8 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.849G>T	p.Gln283His	missense_variant	Exon 8 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1514 AN: 152260 Hom.: 22 Cov.: 33

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

GnomAD2 exomes AF: 0.00267 AC: 499 AN: 187218 AF XY: 0.00214

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 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.: 18 Cov.: 34 AF XY: 0.000878 AC XY: 617 AN XY: 702946

African (AFR) AF: 0.0357 AC: 1170 AN: 32806

American (AMR) AF: 0.00229 AC: 87 AN: 37926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37874

South Asian (SAS) AF: 0.0000852 AC: 7 AN: 82130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50322

Middle Eastern (MID) AF: 0.00119 AC: 6 AN: 5052

European-Non Finnish (NFE) AF: 0.0000275 AC: 30 AN: 1090780

Other (OTH) AF: 0.00194 AC: 114 AN: 58796

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152378 Hom.: 22 Cov.: 33 AF XY: 0.0102 AC XY: 758 AN XY: 74514

African (AFR) AF: 0.0349 AC: 1453 AN: 41592

American (AMR) AF: 0.00359 AC: 55 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00241 Hom.: 6

Bravo AF: 0.0116

ESP6500AA AF: 0.0324 AC: 142

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00252 AC: 303

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

- -

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

- -

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. -

May 26, 2016

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

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) -

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. -

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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. -

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 -

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	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	.;.;T;T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.0	N;.;.;N
PhyloP100		0.98
PrimateAI	Benign	0.25	T
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	T
GERP RS		2.1
Varity_R		0.094
gMVP		0.50
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs113282414; hg19: chr19-50905877; COSMIC: COSV70953898; COSMIC: COSV70953898;