rs145473716

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002691.4(POLD1):c.2275G>A(p.Val759Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,609,734 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 18 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:16

Conservation

PhyloP100: 9.20

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017968148).

BP6

Variant 19-50413766-G-A is Benign according to our data. Variant chr19-50413766-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221038.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=5, Uncertain_significance=3}. Variant chr19-50413766-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.2275G>A	p.Val759Ile	missense_variant	Exon 19 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.2275G>A	p.Val759Ile	missense_variant	Exon 19 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00184

AC:

456

AN:

247622

Hom.:

AF XY:

0.00184

AC XY:

247

AN XY:

133922

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000671

Gnomad ASJ exome

AF:

0.0203

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.00270

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000969

Gnomad OTH exome

AF:

0.00330

GnomAD4 exome

AF:

0.00118

AC:

1718

AN:

1457410

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

944

AN XY:

725038

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.000743

Gnomad4 ASJ exome

AF:

0.0229

Gnomad4 EAS exome

AF:

0.000756

Gnomad4 SAS exome

AF:

0.00286

Gnomad4 FIN exome

AF:

0.0000196

Gnomad4 NFE exome

AF:

0.000501

Gnomad4 OTH exome

AF:

0.00249

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152324

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00171

AC:

208

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:5

Feb 26, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.242% (35 South Asian and 150 European alleles) and 2% in gnomAD (207 Ashkenazi alleles - too high for disease prevalence). It is classified in ClinVar with 1 star as Likely benign by 2 submitters (Invitae, Vantari) and as VUS by GeneDx. -

Apr 18, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 p.Val759Ile variant was identified in 4 of 84 proband chromosomes (frequency: 0.0476) from individuals or families with early-onset colon cancer (Rosner_2015). The variant was also identified in dbSNP (ID: rs145473716) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (as benign by Invitae, as likely benign by Vantari Genetics, GeneDx, Partners Health Care Personalized Medicine, Quest Diagnostics, and Ambry Genetics, and as uncertain significance by Counsyl), Clinvitae (3x), and Cosmic (in somatic tumours in the large intestine and central nervous system). The variant was not identified in the MutDB database. The variant was identified in control databases in 461 of 273426 chromosomes (8 homozygous) at a frequency of 0.001686 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24014 chromosomes (freq: 0.000042), Other in 12 of 6404 chromosomes (freq: 0.001874), Latino in 21 of 34128 chromosomes (freq: 0.000615), European (Non-Finnish) in 116 of 125376 chromosomes (freq: 0.000925), Ashkenazi Jewish in 209 of 9996 chromosomes (freq: 0.02091), East Asian in 19 of 18792 chromosomes (freq: 0.001011), and South Asian in 83 of 30524 chromosomes (freq: 0.002719), while the variant was not observed in the European (Finnish) populations. Interestingly, in a study of genetic variants that cause longevity, the p.Val759Ile variant was found in 14 controls and 17 centenarians (individuals over 105 years old) (Han_2013_23376243). The p.Val759 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Colorectal cancer, susceptibility to, 10

Uncertain:2Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Nov 04, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Sep 29, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 20, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 26, 2015

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Apr 05, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25986922, 25822476, 23376243, 27153395, 30086056) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLD1: BS2 -

POLD1-related disorder

Benign:1

Aug 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Benign

0.083

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.8

M;.;.;M

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.0

N;.;.;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.52

MVP

0.56

MPC

1.5

ClinPred

0.059

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.52

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