19-50401916-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_002691.4(POLD1):c.455C>T(p.Ala152Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A152S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9

Conservation

PhyloP100: 1.71

Publications

8 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04330492).

BP6

Variant 19-50401916-C-T is Benign according to our data. Variant chr19-50401916-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239348.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.455C>T	p.Ala152Val	missense_variant	Exon 4 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.455C>T	p.Ala152Val	missense_variant	Exon 4 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000474

AC:

119

AN:

251100

AF XY:

0.000435

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000811

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000594

AC:

869

AN:

1461774

Hom.:

Cov.:

AF XY:

0.000609

AC XY:

443

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.000492

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000716

AC:

796

AN:

1111948

Other (OTH)

AF:

0.000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000598

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41570

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000796

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 18, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

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 -

Dec 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25620207) -

not specified

Uncertain:2Benign:1

Aug 16, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POLD1 c.455C>T (p.Ala152Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251100 control chromosomes. The observed variant frequency is approximately 33.36 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05). c.455C>T has been reported in the literature in individuals with a personal or family history of hereditary cancer (e.g. Guindalini_2022, Bhai_2021, de Oliveira_2022, Erdem_2020, Mur_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 32283892, 35264596, 32792570, 37990341, 35534704). ClinVar contains an entry for this variant (Variation ID: 239348). Based on the evidence outlined above, the variant was classified as likely benign. -

Feb 17, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.455C>T, in exon 4 that results in an amino acid change, p.Ala152Val. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has been described in the gnomAD database with a frequency of 0.09% in the European sub-population (dbSNP rs41563714). The p.Ala152Val change affects a highly conserved amino acid residue located in a domain of the POLD1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala152Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala152Val change remains unknown at this time. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 10

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 18, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 28, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

POLD1-related disorder

Benign:1

Sep 23, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;.;.;.;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

.;.;D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.043

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

L;.;.;.;L

PhyloP100

1.7

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.25

T;.;.;.;.

Sift4G

Benign

0.43

T;T;D;T;T

Polyphen

0.042

B;.;.;.;B

Vest4

0.34

MVP

0.49

MPC

0.35

ClinPred

0.014

GERP RS

4.0

Varity_R

0.16

gMVP

0.52

Mutation Taster

=56/44

polymorphism

(source)

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

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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