rs1726801

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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:8

Conservation

PhyloP100: -0.744

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=0.0053633153).

BP6

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

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/exons	MANE	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.356G>A	p.Arg119His	missense_variant	4/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.356G>A	p.Arg119His	missense_variant	4/27	1	NM_002691.4	P1

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

GnomAD3 exomes

AF:

0.111

AC:

27583

AN:

249360

Hom.:

2111

AF XY:

0.112

AC XY:

15135

AN XY:

135136

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 SAS exome

AF:

0.200

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

Gnomad4 AFR exome

AF:

0.295

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.166

Gnomad4 SAS exome

AF:

0.197

Gnomad4 FIN exome

AF:

0.0413

Gnomad4 NFE exome

AF:

0.0692

Gnomad4 OTH exome

AF:

0.0994

GnomAD4 genome

AF:

0.139

AC:

21117

AN:

152108

Hom.:

2213

Cov.:

AF XY:

0.138

AC XY:

10244

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.291

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.153

Gnomad4 SAS

AF:

0.200

Gnomad4 FIN

AF:

0.0359

Gnomad4 NFE

AF:

0.0670

Gnomad4 OTH

AF:

0.127

Alfa

AF:

0.0888

Hom.:

1058

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2015	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. -

Colorectal cancer, susceptibility to, 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Mandibular hypoplasia-deafness-progeroid syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 18, 2016

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. -

Hereditary cancer-predisposing syndrome

Benign:1

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. -

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

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

MutationTaster

Benign

1.0

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

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