19-50407153-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_002691.4(POLD1):c.1665C>T(p.Val555Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,607,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V555V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 4 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -1.54

Publications

1 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 19-50407153-C-T is Benign according to our data. Variant chr19-50407153-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.54 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.1665C>T	p.Val555Val	synonymous_variant	Exon 13 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.1665C>T	p.Val555Val	synonymous_variant	Exon 13 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000783

AC:

194

AN:

247632

AF XY:

0.000858

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000517

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.00102

AC:

1487

AN:

1455658

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

776

AN XY:

723070

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33374

American (AMR)

AF:

0.00

AC:

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

25978

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.00177

AC:

152

AN:

86088

European-Finnish (FIN)

AF:

0.000512

AC:

AN:

52708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00112

AC:

1239

AN:

1107762

Other (OTH)

AF:

0.000999

AC:

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000571

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41570

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00228

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68022

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000992

Hom.:

Bravo

AF:

0.000536

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.000890

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 30, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 28, 2017

GeneDx

Significance:Likely 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. -

Jan 07, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2017

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLD1: BP4, BP7 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 26, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Oct 01, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jun 18, 2015

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. -

Apr 06, 2018

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 10

Benign:2

Feb 07, 2025

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLD1 p.Val555= variant was not identified in the literature. The variant was identified in dbSNP (rs150238541) as â€šÃ„Ãºwith likely benign alleleâ€šÃ„Ã¹ and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, True Health Diagnostics and 2 other submitters; and as benign by Invitae and Prevention Genetics). The variant was identified in control databases in 206 of 279,020 chromosomes (2 homozygous) at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 43 of 30,490 chromosomes (freq: 0.001), European in 142 of 126,522 chromosomes (freq: 0.001), Other in 4 of 7138 chromosomes (freq: 0.0006), Finnish in 13 of 24,740 chromosomes (freq: 0.0005), Ashkenazi Jewish in 1 of 10,192 chromosomes (freq: 0.0001), African in 2 of 24,900 chromosomes (freq: 0.00008), and Latino in 1 of 35,130 chromosomes (freq: 0.00003), while it was not observed in the East Asian population. The p.Val555= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.6

(source)

DANN

Benign

0.52

PhyloP100

-1.5

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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