19-50415724-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002691.4(POLD1):c.2718G>T(p.Arg906Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R906K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLD1
NM_002691.4 missense, splice_region

Scores

Splicing: ADA: 0.9971

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.60

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2718G>T	p.Arg906Ser	missense splice_region	Exon 22 of 27	NP_002682.2
POLD1	NM_001308632.1		c.2796G>T	p.Arg932Ser	missense splice_region	Exon 21 of 26	NP_001295561.1
POLD1	NM_001256849.1		c.2718G>T	p.Arg906Ser	missense splice_region	Exon 22 of 27	NP_001243778.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.2718G>T	p.Arg906Ser	missense splice_region	Exon 22 of 27	ENSP00000406046.1
POLD1	ENST00000595904.6	TSL:1	c.2796G>T	p.Arg932Ser	missense splice_region	Exon 22 of 27	ENSP00000472445.1
POLD1	ENST00000599857.7	TSL:1	c.2718G>T	p.Arg906Ser	missense splice_region	Exon 22 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1340438

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

662136

African (AFR)

AF:

0.00

AC:

AN:

30730

American (AMR)

AF:

0.00

AC:

AN:

34568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23018

East Asian (EAS)

AF:

0.00

AC:

AN:

33252

South Asian (SAS)

AF:

0.00

AC:

AN:

79110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3800

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045838

Other (OTH)

AF:

0.00

AC:

AN:

54036

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10

Uncertain:1

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 906 of the POLD1 protein (p.Arg906Ser). This variant is not present in population databases (gnomAD no frequency). 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: 537080). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Uncertain:1

Sep 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R906S variant (also known as c.2718G>T) is located in coding exon 21 of the POLD1 gene. The arginine at codon 906 is replaced by serine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 21. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

4.1

PhyloP100

2.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.94

Vest4

0.66

MutPred

0.70

Gain of phosphorylation at R906 (P = 0.0362)

MVP

0.55

MPC

1.7

ClinPred

1.0

GERP RS

2.0

PromoterAI

-0.0088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.78

gMVP

0.81

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over