chr19-50414972-G-A

Variant names:

• chr19-50414972-G-A
• rs3218775
• NM_002691.4:c.2546G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002691.4(POLD1):​c.2546G>A​(p.Arg849His) variant causes a missense change. The variant allele was found at a frequency of 0.00734 in 1,590,186 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts 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. R849C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (65 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 3.81
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074485242).
• BP6: Variant 19-50414972-G-A is Benign according to our data. Variant chr19-50414972-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00742 (10666/1437878) while in subpopulation MID AF = 0.0189 (108/5706). AF 95% confidence interval is 0.016. There are 65 homozygotes in GnomAdExome4. There are 5256 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2546G>A	p.Arg849His	missense_variant	Exon 20 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2546G>A	p.Arg849His	missense_variant	Exon 20 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1014 AN: 152190 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00783 AC: 1714 AN: 218902 AF XY: 0.00796

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00778

Gnomad NFE exome AF: 0.00890

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00742 AC: 10666 AN: 1437878 Hom.: 65 Cov.: 32 AF XY: 0.00736 AC XY: 5256 AN XY: 713736

African (AFR) AF: 0.00119 AC: 39 AN: 32814

American (AMR) AF: 0.00770 AC: 323 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.0436 AC: 1103 AN: 25312

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38530

South Asian (SAS) AF: 0.00177 AC: 149 AN: 83992

European-Finnish (FIN) AF: 0.00735 AC: 375 AN: 51010

Middle Eastern (MID) AF: 0.0189 AC: 108 AN: 5706

European-Non Finnish (NFE) AF: 0.00732 AC: 8047 AN: 1099290

Other (OTH) AF: 0.00877 AC: 520 AN: 59268

GnomAD4 genome AF: 0.00664 AC: 1012 AN: 152308 Hom.: 10 Cov.: 33 AF XY: 0.00650 AC XY: 484 AN XY: 74476

African (AFR) AF: 0.00140 AC: 58 AN: 41562

American (AMR) AF: 0.0101 AC: 155 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 155 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00769 AC: 523 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00782 Hom.: 19

Bravo AF: 0.00685

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00672 AC: 814

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

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

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 22, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:5

Sep 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 25, 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 c.2546G>A (p.Arg849His) in POLD1 gene is a missense change that involves a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.01 (728/69008 chrs tested) including 4 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant is cited as Benign/Polymorphism by a reputable database/clinical laboratory and published report. Taking together, the variant was classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLD1: BS2 -

Hereditary cancer-predisposing syndrome Benign:4

May 20, 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. -

May 11, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 12, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 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.2624G>A (p.Arg875His) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 220865 as of 2025-01-02).There is a small physicochemical difference between arginine 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 -

Colorectal cancer, susceptibility to, 10 Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 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. -

Carcinoma of colon 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.Arg849His variant was identified in 2 of 58 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer (Talseth-Palmer 2016). The variant was also identified in dbSNP (ID: rs3218775 as With Likely benign allele), ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and two other clinical laboratories), and LOVD 3.0 (classified as benign and likely benign). The variant was not identified in Cosmic, or MutDB. The variant was identified in control databases in 1854 of 245284 chromosomes (13 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). This variant was seen in the following populations: African in 27 of 21986 chromosomes (freq: 0.001), Other in 63 of 5744 chromosomes (freq: 0.01), Latino in 209 of 30752 chromosomes (freq: 0.01), European Non-Finnish in 954 of 110672 chromosomes (freq: 0.01), Ashkenazi Jewish in 383 of 9020 chromosomes (freq: 0.04), European Finnish in 174 of 22218 chromosomes (freq: 0.01), and South Asian in 44 of 28122 chromosomes (freq: 0.002); it was not observed in the East Asian population. The p.Arg849 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role. This variant is classified as likely benign. -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

Oct 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.97	.;.;D;D
MetaRNN	Benign	0.0074	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L;.;.;L
PhyloP100		3.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;.;.;.
REVEL	Benign	0.052
Sift	Benign	0.36	T;.;.;.
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.025	B;.;.;B
Vest4		0.17
MVP		0.48
MPC		0.78
ClinPred		0.0068	T
GERP RS		3.5
Varity_R		0.061
gMVP		0.38
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs3218775; hg19: chr19-50918229;