rs3218773

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 27 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 3.22

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 -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 [Likely_benign]. Clinvar id is 221055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50398907-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.56G>A	p.Arg19His	missense_variant	2/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.56G>A	p.Arg19His	missense_variant	2/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152268

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00539

AC:

1222

AN:

226642

Hom.:

AF XY:

0.00471

AC XY:

575

AN XY:

121972

show subpopulations

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 SAS exome

AF:

0.000611

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.:

Cov.:

AF XY:

0.00144

AC XY:

1034

AN XY:

719010

show subpopulations

Gnomad4 AFR exome

AF:

0.000690

Gnomad4 AMR exome

AF:

0.0154

Gnomad4 ASJ exome

AF:

0.00234

Gnomad4 EAS exome

AF:

0.0275

Gnomad4 SAS exome

AF:

0.000667

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000201

Gnomad4 OTH exome

AF:

0.00243

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152386

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00699

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0353

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00339

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00410

AC:

497

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	POLD1: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2015	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 30, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 11, 2015	- -

Colorectal cancer, susceptibility to, 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

Endometrial carcinoma

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;.;.;T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.78

.;.;T;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.;.;N;.

MutationTaster

Benign

0.78

PrimateAI

Uncertain

0.67

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

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.053

gMVP

0.25

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

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