NM_002691.4:c.2773G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002691.4(POLD1):c.2773G>A(p.Val925Met) variant causes a missense change. The variant allele was found at a frequency of 0.000014 in 1,566,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V925L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.01

Publications

3 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 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

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.2773G>A	p.Val925Met	missense	Exon 22 of 27	NP_002682.2
POLD1	NM_001308632.1		c.2851G>A	p.Val951Met	missense	Exon 21 of 26	NP_001295561.1
POLD1	NM_001256849.1		c.2773G>A	p.Val925Met	missense	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.2773G>A	p.Val925Met	missense	Exon 22 of 27	ENSP00000406046.1
POLD1	ENST00000595904.6	TSL:1	c.2851G>A	p.Val951Met	missense	Exon 22 of 27	ENSP00000472445.1
POLD1	ENST00000599857.7	TSL:1	c.2773G>A	p.Val925Met	missense	Exon 22 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150672

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

185020

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000135

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000148

AC:

AN:

1415778

Hom.:

Cov.:

AF XY:

0.00000714

AC XY:

AN XY:

700656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32782

American (AMR)

AF:

0.00

AC:

AN:

39036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24912

East Asian (EAS)

AF:

0.000236

AC:

AN:

38156

South Asian (SAS)

AF:

0.00

AC:

AN:

80518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

1090704

Other (OTH)

AF:

0.00

AC:

AN:

58434

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00000664

AC:

AN:

150672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41130

American (AMR)

AF:

0.00

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5006

South Asian (SAS)

AF:

0.00

AC:

AN:

4680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67610

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.0000712

Hom.:

ExAC

AF:

0.00000845

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Colorectal cancer, susceptibility to, 10 (2)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.015

MutationAssessor

Pathogenic

5.0

PhyloP100

6.0

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MutPred

0.76

Gain of disorder (P = 0.0739)

MVP

0.71

MPC

1.6

ClinPred

1.0

GERP RS

3.3

PromoterAI

-0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.81

Mutation Taster

=36/64

disease causing

(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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over