rs137953986

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002691.4(POLD1):c.433G>A(p.Ala145Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,613,944 control chromosomes in the GnomAD database, including 7 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 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 6 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 3.72

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:

POLD1 (HGNC:):

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011245161).

BP6

Variant 19-50401894-G-A is Benign according to our data. Variant chr19-50401894-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 221138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50401894-G-A is described in Lovd as [Benign]. Variant chr19-50401894-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 364 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.433G>A	p.Ala145Thr	missense_variant	4/27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.433G>A	p.Ala145Thr	missense_variant	4/27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00268

AC:

674

AN:

251270

Hom.:

AF XY:

0.00264

AC XY:

359

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00271

AC:

3967

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00268

AC XY:

1948

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.00270

Gnomad4 OTH exome

AF:

0.00233

GnomAD4 genome

AF:

0.00239

AC:

364

AN:

152156

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0126

Gnomad4 NFE

AF:

0.00265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00152

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00254

AC:

308

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2016	Variant summary: The POLD1 c.433G>A (p.Ala145Thr) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is located in the Ribonuclease H-like domain (InterPro).This variant was found in 308/121298 control chromosomes (2 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.012269 (81/6602). This frequency is about 864 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In a non-peer reviewed project report this variant was reported to be found in 3/95 CRC patients (Rypdal KB, 2015). Another missense change at the same residue p.A145D has also been found in one CRC patient who did not have somatic pathogenic variants (PMID 23263490). Although it is not monogenically linked to CRC phenotype based on population data, whether this variant represents a risk allele needs to be further examined by case-control studies. There are no published functional studies. In ClinVar, while one clinical lab classifies it as uncertain significance, another as benign. Taken together, this variant is currently classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	POLD1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is associated with the following publications: (PMID: 21796119, 28608266) -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Colorectal cancer, susceptibility to, 10

Benign:2

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

POLD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

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). -

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

Nov 04, 2021

- -

Familial ovarian cancer

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLD1 p.Ala145Thr variant was not identified in the literature. The variant was identified in dbSNP (ID: rs137953986 as "With Likely benign allele"), ClinVar (classified as benign by Invitae; and as likely benign by Ambry Genetics, GeneDx and four other submitters), and in LOVD 3.0 (2x as benign and likely benign). The variant was identified in control databases in 767 of 276920 chromosomes (4 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 23990 chromosomes (freq: 0.0003), Other in 13 of 6454 chromosomes (freq: 0.002), Latino in 5 of 34416 chromosomes (freq: 0.0002), European in 340 of 126504 chromosomes (freq: 0.003), Ashkenazi Jewish in 1 of 10134 chromosomes (freq: 0.0001), East Asian in 1 of 18866 chromosomes (freq: 0.00005), Finnish in 341 of 25774 chromosomes (freq: 0.01), and South Asian in 59 of 30782 chromosomes (freq: 0.002). The p.Ala145 residue is conserved in mammals but not in more distantly related organisms. However, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Colon cancer

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 47 year old with a history of colon cancer diagnosed at 47 and a family history of colon cancer. In exonuclease domain. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2018

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

0.084

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.10

T;.;.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

.;.;D;D;D

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.48

N;.;.;.;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.42

N;.;.;.;.

REVEL

Benign

0.096

Sift

Benign

0.61

T;.;.;.;.

Sift4G

Benign

0.73

T;T;D;T;T

Polyphen

0.068

B;.;.;.;B

Vest4

0.52

MVP

0.43

MPC

0.20

ClinPred

0.0094

GERP RS

4.0

Varity_R

0.10

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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