rs1726801

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002691.4(POLD1):c.356G>A(p.Arg119His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,613,260 control chromosomes in the GnomAD database, including 9,626 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 2213 hom., cov: 32)

Exomes 𝑓: 0.087 ( 7413 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.744

Publications

54 publications found

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 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

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053633153).

BP6

Variant 19-50401817-G-A is Benign according to our data. Variant chr19-50401817-G-A is described in ClinVar as Benign. ClinVar VariationId is 380220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.356G>A	p.Arg119His	missense_variant	Exon 4 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.356G>A	p.Arg119His	missense_variant	Exon 4 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21083

AN:

151988

Hom.:

2207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.291

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.0359

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0670

Gnomad OTH

AF:

0.128

GnomAD2 exomes

AF:

0.111

AC:

27583

AN:

249360

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.298

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.139

Gnomad FIN exome

AF:

0.0405

Gnomad NFE exome

AF:

0.0703

Gnomad OTH exome

AF:

0.0994

GnomAD4 exome

AF:

0.0869

AC:

126919

AN:

1461152

Hom.:

7413

Cov.:

AF XY:

0.0901

AC XY:

65476

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.295

AC:

9860

AN:

33470

American (AMR)

AF:

0.105

AC:

4701

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2762

AN:

26106

East Asian (EAS)

AF:

0.166

AC:

6589

AN:

39696

South Asian (SAS)

AF:

0.197

AC:

17017

AN:

86234

European-Finnish (FIN)

AF:

0.0413

AC:

2187

AN:

52998

Middle Eastern (MID)

AF:

0.146

AC:

841

AN:

5762

European-Non Finnish (NFE)

AF:

0.0692

AC:

76962

AN:

1111816

Other (OTH)

AF:

0.0994

AC:

6000

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

6161

12321

18482

24642

30803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3164

6328

9492

12656

15820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.139

AC:

21117

AN:

152108

Hom.:

2213

Cov.:

AF XY:

0.138

AC XY:

10244

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.291

AC:

12056

AN:

41472

American (AMR)

AF:

0.103

AC:

1574

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

367

AN:

3472

East Asian (EAS)

AF:

0.153

AC:

789

AN:

5164

South Asian (SAS)

AF:

0.200

AC:

962

AN:

4818

European-Finnish (FIN)

AF:

0.0359

AC:

380

AN:

10596

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0670

AC:

4554

AN:

67976

Other (OTH)

AF:

0.127

AC:

269

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

822

1643

2465

3286

4108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0964

Hom.:

2033

Bravo

AF:

0.150

TwinsUK

AF:

0.0763

AC:

283

ALSPAC

AF:

0.0682

AC:

263

ESP6500AA

AF:

0.296

AC:

1305

ESP6500EA

AF:

0.0720

AC:

619

ExAC

AF:

0.114

AC:

13861

Asia WGS

AF:

0.186

AC:

645

AN:

3478

EpiCase

AF:

0.0748

EpiControl

AF:

0.0763

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 06, 2015

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 02, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided

Benign:2

May 18, 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.356G>A (p.Arg119His) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 13802/119582 control chromosomes (1139 homozygotes) at a frequency of 0.1154187, which is approximately 8125 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Colorectal cancer, susceptibility to, 10

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Dec 23, 2024

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.356G>A (p.Arg119His) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380220 as of 2024-12-05). The p.Arg119His variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Arg119His missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The histidine residue at codon 119 of POLD1 is present in Orangutan and 4 other mammalian species. The nucleotide c.356 in POLD1 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -

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. -

Mandibular hypoplasia-deafness-progeroid syndrome

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0070

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.17

T;.;.;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.17

.;.;T;T;T

MetaRNN

Benign

0.0054

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.97

L;.;.;.;L

PhyloP100

-0.74

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.37

N;.;.;.;.

REVEL

Benign

0.011

Sift

Benign

0.33

T;.;.;.;.

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.0010

B;.;.;.;B

Vest4

0.020

MPC

0.23

ClinPred

0.0037

GERP RS

-8.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.012

gMVP

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over