19-50417187-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_002691.4(POLD1):c.3136G>T(p.Ala1046Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000623 in 1,606,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A1046V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.488

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:

ENSG00000142539 (HGNC:):

ENSG00000142539 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08272156).

BP6

Variant 19-50417187-G-T is Benign according to our data. Variant chr19-50417187-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407978.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLD1	NM_002691.4	MANE Select	c.3136G>T	p.Ala1046Ser	missense	Exon 26 of 27	NP_002682.2
POLD1	NM_001308632.1		c.3214G>T	p.Ala1072Ser	missense	Exon 25 of 26	NP_001295561.1
POLD1	NM_001256849.1		c.3136G>T	p.Ala1046Ser	missense	Exon 26 of 27	NP_001243778.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.3136G>T	p.Ala1046Ser	missense	Exon 26 of 27	ENSP00000406046.1
POLD1	ENST00000595904.6	TSL:1	c.3214G>T	p.Ala1072Ser	missense	Exon 26 of 27	ENSP00000472445.1
POLD1	ENST00000599857.7	TSL:1	c.3136G>T	p.Ala1046Ser	missense	Exon 26 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000212

AC:

AN:

236014

AF XY:

0.0000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000467

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000667

AC:

AN:

1454056

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

722942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

44070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25872

East Asian (EAS)

AF:

0.00

AC:

AN:

39458

South Asian (SAS)

AF:

0.00

AC:

AN:

85200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000838

AC:

AN:

1109320

Other (OTH)

AF:

0.0000666

AC:

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000596

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

POLD1-related disorder

Uncertain:1

Dec 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLD1 c.3136G>T variant is predicted to result in the amino acid substitution p.Ala1046Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0049% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/407978/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Carcinoma of colon

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLD1 p.Ala1046Ser variant was not identified in the literature nor was it identified in the Cosmic or MutDB database. The variant was identified in dbSNP (ID: rs751088347) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae). The variant was identified in a control database in 8 of 262252 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 8 of 120228 chromosomes (freq: 0.0001), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala1046 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.

not provided

Uncertain:1

Oct 27, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19296856)

Colorectal cancer, susceptibility to, 10

Uncertain:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1046 of the POLD1 protein (p.Ala1046Ser). This variant is present in population databases (rs751088347, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407978). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Hereditary cancer-predisposing syndrome

Benign:1

Mar 07, 2024

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.078

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.041

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.23

PhyloP100

0.49

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.010

REVEL

Benign

0.036

Sift

Benign

0.40

Sift4G

Benign

0.52

Polyphen

0.0050

Vest4

0.21

MutPred

0.36

Gain of disorder (P = 0.017)

MVP

0.40

MPC

0.59

ClinPred

0.075

GERP RS

3.1

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.0

Varity_R

0.10

gMVP

0.22

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over