rs748657880

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_002691.4(POLD1):c.868G>A(p.Val290Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000632 in 1,581,980 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V290L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.38

Publications

2 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 -1 ACMG points.

BP6

Variant 19-50402639-G-A is Benign according to our data. Variant chr19-50402639-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505437.

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.868G>A	p.Val290Met	missense	Exon 8 of 27	NP_002682.2
POLD1	NM_001308632.1		c.868G>A	p.Val290Met	missense	Exon 7 of 26	NP_001295561.1
POLD1	NM_001256849.1		c.868G>A	p.Val290Met	missense	Exon 8 of 27	NP_001243778.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.868G>A	p.Val290Met	missense	Exon 8 of 27	ENSP00000406046.1
POLD1	ENST00000595904.6	TSL:1	c.868G>A	p.Val290Met	missense	Exon 8 of 27	ENSP00000472445.1
POLD1	ENST00000599857.7	TSL:1	c.868G>A	p.Val290Met	missense	Exon 8 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000248

AC:

AN:

201364

AF XY:

0.0000184

show subpopulations

Gnomad AFR exome

AF:

0.0000821

Gnomad AMR exome

AF:

0.0000704

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000230

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000629

AC:

AN:

1429708

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

708018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33052

American (AMR)

AF:

0.0000509

AC:

AN:

39292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.00

AC:

AN:

38458

South Asian (SAS)

AF:

0.00

AC:

AN:

83128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5032

European-Non Finnish (NFE)

AF:

0.00000548

AC:

AN:

1095456

Other (OTH)

AF:

0.0000169

AC:

AN:

59118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00000657

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74396

show subpopulations

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

African (AFR)

AF:

0.0000241

AC:

AN:

41476

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:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ 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:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000414

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Colorectal cancer, susceptibility to, 10 (1)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

3.4

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Benign

0.056

Sift4G

Benign

0.089

Polyphen

0.90

Vest4

0.67

MutPred

0.60

Loss of sheet (P = 0.0315)

MVP

0.52

MPC

0.74

ClinPred

0.43

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.73

Mutation Taster

=73/27

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

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over