Genetic Variant POLD1:p.Ser748Ser (chr19-50413515-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002691.4(POLD1):c.2244T>C(p.Ser748Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,607,560 control chromosomes in the GnomAD database, including 4,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 2474 hom., cov: 33)

Exomes 𝑓: 0.013 ( 2207 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.99

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-50413515-T-C is Benign according to our data. Variant chr19-50413515-T-C is described in ClinVar as Benign. ClinVar VariationId is 380228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 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.2244T>C	p.Ser748Ser	synonymous	Exon 18 of 27	NP_002682.2	P28340
POLD1	NM_001308632.1		c.2322T>C	p.Ser774Ser	synonymous	Exon 17 of 26	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.2244T>C	p.Ser748Ser	synonymous	Exon 18 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.2244T>C	p.Ser748Ser	synonymous	Exon 18 of 27	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.2322T>C	p.Ser774Ser	synonymous	Exon 18 of 27	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.2244T>C	p.Ser748Ser	synonymous	Exon 18 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

AF:

0.0994

AC:

15117

AN:

152018

Hom.:

2458

Cov.:

show subpopulations

Gnomad AFR

AF:

0.334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0452

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0458

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.0790

GnomAD2 exomes

AF:

0.0315

AC:

7538

AN:

239014

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.342

Gnomad AMR exome

AF:

0.0200

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.000984

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00183

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0131

AC:

19027

AN:

1455424

Hom.:

2207

Cov.:

AF XY:

0.0126

AC XY:

9102

AN XY:

723730

show subpopulations

African (AFR)

AF:

0.342

AC:

11338

AN:

33188

American (AMR)

AF:

0.0225

AC:

984

AN:

43764

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

559

AN:

26068

East Asian (EAS)

AF:

0.000713

AC:

AN:

39264

South Asian (SAS)

AF:

0.0372

AC:

3184

AN:

85594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.0219

AC:

126

AN:

5760

European-Non Finnish (NFE)

AF:

0.000993

AC:

1101

AN:

1108866

Other (OTH)

AF:

0.0284

AC:

1707

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

768

1536

2305

3073

3841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.0998

AC:

15183

AN:

152136

Hom.:

2474

Cov.:

AF XY:

0.0971

AC XY:

7227

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.334

AC:

13857

AN:

41474

American (AMR)

AF:

0.0450

AC:

688

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5170

South Asian (SAS)

AF:

0.0461

AC:

222

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00196

AC:

133

AN:

67982

Other (OTH)

AF:

0.0829

AC:

175

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

530

1059

1589

2118

2648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0416

Hom.:

2457

Bravo

AF:

0.113

Asia WGS

AF:

0.0700

AC:

245

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Colorectal cancer, susceptibility to, 10 (2)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.23

(source)

DANN

Benign

0.45

PhyloP100

-2.0

PromoterAI

0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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