Genetic Variant NM_002691.4:c.2967G>A (chr19-50416623-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4BP6_Very_StrongBP7BS2

The NM_002691.4(POLD1):c.2967G>A(p.Thr989Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,563,834 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T989T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0029 ( 6 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -3.95

Publications

4 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:

ENSG00000142539 (HGNC:):

ENSG00000142539 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.187).

BP6

Variant 19-50416623-G-A is Benign according to our data. Variant chr19-50416623-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.95 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 6 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.2967G>A	p.Thr989Thr	synonymous	Exon 24 of 27	NP_002682.2	P28340
POLD1	NM_001308632.1		c.3045G>A	p.Thr1015Thr	synonymous	Exon 23 of 26	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.2967G>A	p.Thr989Thr	synonymous	Exon 24 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.2967G>A	p.Thr989Thr	synonymous	Exon 24 of 27	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.3045G>A	p.Thr1015Thr	synonymous	Exon 24 of 27	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.2967G>A	p.Thr989Thr	synonymous	Exon 24 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000752

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00146

AC:

247

AN:

168900

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.000765

Gnomad AMR exome

AF:

0.000186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000512

Gnomad NFE exome

AF:

0.00274

Gnomad OTH exome

AF:

0.00108

GnomAD4 exome

AF:

0.00286

AC:

4033

AN:

1411548

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

1880

AN XY:

698708

show subpopulations

African (AFR)

AF:

0.000527

AC:

AN:

32264

American (AMR)

AF:

0.000210

AC:

AN:

38018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25302

East Asian (EAS)

AF:

0.00

AC:

AN:

36920

South Asian (SAS)

AF:

0.00124

AC:

100

AN:

80724

European-Finnish (FIN)

AF:

0.000614

AC:

AN:

43984

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5268

European-Non Finnish (NFE)

AF:

0.00345

AC:

3760

AN:

1090440

Other (OTH)

AF:

0.00205

AC:

120

AN:

58628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

208

416

625

833

1041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00140

AC:

213

AN:

152286

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41554

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000752

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00256

AC:

174

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.00204

Hom.:

Bravo

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (6)

Colorectal cancer, susceptibility to, 10 (3)

Hereditary cancer-predisposing syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.11

(source)

DANN

Benign

0.85

PhyloP100

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over