rs3218772

Positions:

chr19-50398939-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_002691.4(POLD1):c.88C>T(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,593,262 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 124 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.865

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 -12 ACMG points.

BP6

Variant 19-50398939-C-T is Benign according to our data. Variant chr19-50398939-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 221163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50398939-C-T is described in Lovd as [Benign]. Variant chr19-50398939-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1085 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.88C>T	p.Arg30Trp	missense_variant	2/27	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.88C>T	p.Arg30Trp	missense_variant	2/27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1085

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00821

AC:

1770

AN:

215634

Hom.:

AF XY:

0.00887

AC XY:

1023

AN XY:

115286

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00649

Gnomad ASJ exome

AF:

0.00806

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.00271

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0108

AC:

15496

AN:

1440938

Hom.:

124

Cov.:

AF XY:

0.0108

AC XY:

7736

AN XY:

714662

show subpopulations

Gnomad4 AFR exome

AF:

0.00238

Gnomad4 AMR exome

AF:

0.00694

Gnomad4 ASJ exome

AF:

0.00794

Gnomad4 EAS exome

AF:

0.0000512

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.00302

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00712

AC:

1085

AN:

152324

Hom.:

Cov.:

AF XY:

0.00648

AC XY:

483

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00932

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00713

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.00707

AC:

856

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2016	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, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 09, 2016	- -

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLD1 p.Arg30Trp variant was identified in 1 of 58 proband chromosomes (frequency: 0.02) from individuals or families with HNPCC (Talseth-Palmer 2015). The variant was also identified in dbSNP (ID: rs3218772) as "With Benign allele", ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics and three other clinical laboratories), Cosmic (1x in prostate tissue), and MutDB. The variant was identified in control databases in 1935 of 241054 chromosomes (13 homozygous) at a frequency of 0.008, 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: European in 1228 of 108476 chromosomes (freq: 0.01), South Asian in 299 of 26820 chromosomes (freq: 0.01), African in 28 of 21060 chromosomes (freq: 0.001), Other in 62 of 5816 chromosomes (freq: 0.01), Latino in 183 of 30048 chromosomes (freq: 0.006), Ashkenazi Jewish in 74 of 9266 chromosomes (freq: 0.0079), and Finnish in 61 of 22694 chromosomes (freq: 0.0026), while the variant was not observed in the East Asian population. The p.Arg30 residue is not 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POLD1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2016	Variant summary: The c.88C>T (p.Arg30Trp) in POLD1 gene is a missense change that involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.013 (671/52972 chrs tested) including 5 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant was identified in a clinical case, which also carried a known pathogenic mutation, c.68_69delAG, in BRCA1 gene. The variant is cited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign. -

Colorectal cancer, susceptibility to, 10

Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -
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	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
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. -

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

Mar 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;.;T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.47

.;.;T;T;T;T

MetaRNN

Benign

0.0071

T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

N;.;.;.;N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.38

N;.;.;.;.;.

REVEL

Benign

0.028

Sift

Benign

0.043

D;.;.;.;.;.

Sift4G

Uncertain

0.047

D;D;T;D;D;T

Polyphen

0.95

P;.;.;.;P;.

Vest4

0.29

MVP

0.51

MPC

0.29

ClinPred

0.0043

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.041

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: 18

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