Genetic Variant NM_002691.4:c.2103C>T (chr19-50409615-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_002691.4(POLD1):c.2103C>T(p.Tyr701Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,610,402 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 4 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.67

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):

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 19-50409615-C-T is Benign according to our data. Variant chr19-50409615-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.67 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 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.2103C>T	p.Tyr701Tyr	synonymous	Exon 17 of 27	NP_002682.2	P28340
POLD1	NM_001308632.1		c.2181C>T	p.Tyr727Tyr	synonymous	Exon 16 of 26	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.2103C>T	p.Tyr701Tyr	synonymous	Exon 17 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.2103C>T	p.Tyr701Tyr	synonymous	Exon 17 of 27	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.2181C>T	p.Tyr727Tyr	synonymous	Exon 17 of 27	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.2103C>T	p.Tyr701Tyr	synonymous	Exon 17 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

AF:

0.000558

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000800

AC:

200

AN:

250004

AF XY:

0.000967

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.000638

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000894

AC:

1304

AN:

1458028

Hom.:

Cov.:

AF XY:

0.000948

AC XY:

687

AN XY:

724686

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33416

American (AMR)

AF:

0.000291

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00305

AC:

263

AN:

86190

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

52626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.000874

AC:

970

AN:

1109594

Other (OTH)

AF:

0.000648

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.000551

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41598

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00352

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000507

Hom.:

Bravo

AF:

0.000461

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Colorectal cancer, susceptibility to, 10 (2)

Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.5

(source)

DANN

Benign

0.72

PhyloP100

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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