rs3218772

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_002691.4(POLD1):c.88C>T(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,593,262 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 124 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.865

Publications

20 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):

mandibular hypoplasia-deafness-progeroid syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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: Benign. The variant received -12 ACMG points.

BP6

Variant 19-50398939-C-T is Benign according to our data. Variant chr19-50398939-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

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	UniProt
POLD1	NM_002691.4	MANE Select	c.88C>T	p.Arg30Trp	missense	Exon 2 of 27	NP_002682.2	P28340
POLD1	NM_001308632.1		c.88C>T	p.Arg30Trp	missense	Exon 1 of 26	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.88C>T	p.Arg30Trp	missense	Exon 2 of 27	NP_001243778.1	P28340

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.88C>T	p.Arg30Trp	missense	Exon 2 of 27	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.88C>T	p.Arg30Trp	missense	Exon 2 of 27	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.88C>T	p.Arg30Trp	missense	Exon 2 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1085

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00821

AC:

1770

AN:

215634

AF XY:

0.00887

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00649

Gnomad ASJ exome

AF:

0.00806

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00271

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0108

AC:

15496

AN:

1440938

Hom.:

124

Cov.:

AF XY:

0.0108

AC XY:

7736

AN XY:

714662

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

33234

American (AMR)

AF:

0.00694

AC:

286

AN:

41202

Ashkenazi Jewish (ASJ)

AF:

0.00794

AC:

203

AN:

25558

East Asian (EAS)

AF:

0.0000512

AC:

AN:

39076

South Asian (SAS)

AF:

0.0119

AC:

990

AN:

82962

European-Finnish (FIN)

AF:

0.00302

AC:

157

AN:

51996

Middle Eastern (MID)

AF:

0.0155

AC:

AN:

4324

European-Non Finnish (NFE)

AF:

0.0119

AC:

13106

AN:

1103040

Other (OTH)

AF:

0.0102

AC:

606

AN:

59546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

858

1716

2573

3431

4289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.00712

AC:

1085

AN:

152324

Hom.:

Cov.:

AF XY:

0.00648

AC XY:

483

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41566

American (AMR)

AF:

0.00621

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00932

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

796

AN:

68032

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0103

Hom.:

Bravo

AF:

0.00713

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.00707

AC:

856

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (6)

Colorectal cancer, susceptibility to, 10 (3)

Hereditary cancer-predisposing syndrome (3)

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

PhyloP100

0.86

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.38

REVEL

Benign

0.028

Sift

Benign

0.043

Sift4G

Uncertain

0.047

Polyphen

0.95

Vest4

0.29

MVP

0.51

MPC

0.29

ClinPred

0.0043

GERP RS

1.0

PromoterAI

-0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.041

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: 18

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over