rs3218773

Variant names:

• chr19-50398907-G-A
• rs3218773
• NM_002691.4:c.56G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50398907-G-A
• chr19-50398907-G-C
• chr19-50398907-G-T

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.56G>A​(p.Arg19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,600,520 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R19L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (27 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.22
• Publications: 15 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=0.0031368136).
• BP6: Variant 19-50398907-G-A is Benign according to our data. Variant chr19-50398907-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00236 (359/152386) while in subpopulation EAS AF = 0.0353 (183/5190). AF 95% confidence interval is 0.0311. There are 5 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.56G>A	p.Arg19His	missense_variant	Exon 2 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.56G>A	p.Arg19His	missense_variant	Exon 2 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152268 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00539 AC: 1222 AN: 226642 AF XY: 0.00471

Gnomad AFR exome AF: 0.000787

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00300

Gnomad EAS exome AF: 0.0344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000217

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00155 AC: 2246 AN: 1448134 Hom.: 27 Cov.: 33 AF XY: 0.00144 AC XY: 1034 AN XY: 719010

African (AFR) AF: 0.000690 AC: 23 AN: 33320

American (AMR) AF: 0.0154 AC: 658 AN: 42656

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 60 AN: 25692

East Asian (EAS) AF: 0.0275 AC: 1081 AN: 39302

South Asian (SAS) AF: 0.000667 AC: 56 AN: 83954

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4168

European-Non Finnish (NFE) AF: 0.000201 AC: 222 AN: 1106964

Other (OTH) AF: 0.00243 AC: 145 AN: 59746

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152386 Hom.: 5 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74518

African (AFR) AF: 0.000914 AC: 38 AN: 41594

American (AMR) AF: 0.00699 AC: 107 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0353 AC: 183 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00134 Hom.: 5

Bravo AF: 0.00339

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00410 AC: 497

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Jul 13, 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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLD1: BS1, BS2 -

Jul 21, 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.56G>A (p.Arg19His) variant involves the alteration of a non-conserved nucleotide. This variant is located in the nuclear localization signal domain and 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index), however no functional studies supporting these predictions were published at the time of evaluation. This variant was found in 434/63048 control chromosomes (6 homozygotes), observed at relatively higher frequency in the East Asian subpopulation at a frequency of 0.0458626 (235/5124). This frequency is about 3229 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as likely benign/benign. Lastly, the variant was identified internally in one individual with personal and family history of FAP, who tested positive for a pathogenic variant, c.2161_2170delGGAAGTGCTG in APC gene. Taken together, this variant is classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 29, 2024

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:4

Jul 14, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 11, 2015

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Colorectal cancer, susceptibility to, 10 Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Endometrial carcinoma 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.Arg19His variant was identified in 6 of 152 proband chromosomes (frequency: 0.04) from individuals or families with HNPCC and endometrioid endometrial carcinomas (Talseth-Palmer 2015, Wong 2016 ). The variant was also identified in dbSNP (ID: rs3218773) as With Likely benign allele, ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and two clinical laboratories; as likely benign by Vantari Genetics), Clinvitae, and MutDB databases. The variant was identified in control databases in 1238 of 252406 chromosomes (18 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 19 of 21738 chromosomes (freq: 0.001), Other in 24 of 5994 chromosomes (freq: 0.004), Latino in 520 of 31786 chromosomes (freq: 0.02), European in 26 of 114472 chromosomes (freq: 0.0002), Ashkenazi Jewish in 28 of 9430 chromosomes (freq: 0.003), East Asian in 604 of 17564 chromosomes (freq: 0.03), and South Asian in 17 of 27984 chromosomes (freq: 0.001); but not in the Finnish population. The p.Arg19 residue is not conserved in mammals and four out of five 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 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;.;.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.78	.;.;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.
PhyloP100		3.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.
REVEL	Benign	0.048
Sift	Benign	0.058	T;.;.;.;.;.
Sift4G	Benign	0.21	T;T;D;T;T;D
Polyphen		0.0010	B;.;.;.;B;.
Vest4		0.24
MVP		0.43
MPC		0.23
ClinPred		0.018	T
GERP RS		3.1
PromoterAI		-0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.053
gMVP		0.25
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3218773; hg19: chr19-50902164;