dbSNP rs2230247: POLD1:p.Ala516Ala (chr19-50407036-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002691.4(POLD1):c.1548C>T(p.Ala516Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,613,600 control chromosomes in the GnomAD database, including 853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 432 hom., cov: 30)

Exomes 𝑓: 0.0045 ( 421 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.0150

Publications

5 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 19-50407036-C-T is Benign according to our data. Variant chr19-50407036-C-T is described in ClinVar as Benign. ClinVar VariationId is 380637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.015 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

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.1548C>T	p.Ala516Ala	synonymous	Exon 13 of 27	NP_002682.2	P28340
POLD1	NM_001308632.1		c.1548C>T	p.Ala516Ala	synonymous	Exon 12 of 26	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.1548C>T	p.Ala516Ala	synonymous	Exon 13 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.1548C>T	p.Ala516Ala	synonymous	Exon 13 of 27	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.1548C>T	p.Ala516Ala	synonymous	Exon 13 of 27	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.1548C>T	p.Ala516Ala	synonymous	Exon 13 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

6317

AN:

152108

Hom.:

428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0113

AC:

2822

AN:

250414

AF XY:

0.00832

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.00934

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000646

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

AF:

0.00447

AC:

6536

AN:

1461374

Hom.:

421

Cov.:

AF XY:

0.00392

AC XY:

2853

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.149

AC:

4979

AN:

33474

American (AMR)

AF:

0.0104

AC:

465

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00310

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000371

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53020

Middle Eastern (MID)

AF:

0.0110

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000265

AC:

295

AN:

1111942

Other (OTH)

AF:

0.0103

AC:

621

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

278

556

835

1113

1391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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:

0.0417

AC:

6341

AN:

152226

Hom.:

432

Cov.:

AF XY:

0.0403

AC XY:

2996

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.143

AC:

5938

AN:

41480

American (AMR)

AF:

0.0180

AC:

275

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68036

Other (OTH)

AF:

0.0327

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

274

549

823

1098

1372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0229

Hom.:

Bravo

AF:

0.0480

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Hereditary cancer-predisposing syndrome (4)

Colorectal cancer, susceptibility to, 10 (3)

not provided (2)

Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.8

(source)

DANN

Benign

0.56

PhyloP100

0.015

Mutation Taster

=100/0

polymorphism (auto)

(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

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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