12-132643403-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.4444+4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,614,164 control chromosomes in the GnomAD database, including 5,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 329 hom., cov: 34)

Exomes 𝑓: 0.078 ( 4942 hom. )

Consequence

POLE
NM_006231.4 splice_region, intron

Scores

Splicing: ADA: 0.00002649

Clinical Significance

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

Conservation

PhyloP100: 0.304

Publications

12 publications found

Variant links:

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE Gene-Disease associations (from GenCC):

POLE-related polyposis and colorectal cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal cancer, susceptibility to, 12
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
facial dysmorphism-immunodeficiency-livedo-short stature syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
Inheritance: AR Classification: STRONG Submitted by: G2P
IMAGe syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Polymerase proofreading-related adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POLE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 12-132643403-A-T is Benign according to our data. Variant chr12-132643403-A-T is described in CliVar as Benign. Clinvar id is 380213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132643403-A-T is described in CliVar as Benign. Clinvar id is 380213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132643403-A-T is described in CliVar as Benign. Clinvar id is 380213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132643403-A-T is described in CliVar as Benign. Clinvar id is 380213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.4444+4T>A		splice_region_variant, intron_variant	Intron 34 of 48	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.4444+4T>A		splice_region_variant, intron_variant	Intron 34 of 48	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.0563

AC:

8564

AN:

152194

Hom.:

328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.190

Gnomad AMR

AF:

0.0357

Gnomad ASJ

AF:

0.0968

Gnomad EAS

AF:

0.0745

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.0658

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0822

Gnomad OTH

AF:

0.0488

GnomAD2 exomes

AF:

0.0624

AC:

15693

AN:

251402

AF XY:

0.0631

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.0305

Gnomad ASJ exome

AF:

0.0970

Gnomad EAS exome

AF:

0.0749

Gnomad FIN exome

AF:

0.0669

Gnomad NFE exome

AF:

0.0813

Gnomad OTH exome

AF:

0.0762

GnomAD4 exome

AF:

0.0784

AC:

114555

AN:

1461852

Hom.:

4942

Cov.:

AF XY:

0.0769

AC XY:

55936

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0117

AC:

392

AN:

33480

American (AMR)

AF:

0.0308

AC:

1379

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0952

AC:

2488

AN:

26136

East Asian (EAS)

AF:

0.0798

AC:

3168

AN:

39700

South Asian (SAS)

AF:

0.0316

AC:

2722

AN:

86256

European-Finnish (FIN)

AF:

0.0666

AC:

3559

AN:

53400

Middle Eastern (MID)

AF:

0.0569

AC:

328

AN:

5768

European-Non Finnish (NFE)

AF:

0.0862

AC:

95809

AN:

1111994

Other (OTH)

AF:

0.0780

AC:

4710

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

6518

13036

19553

26071

32589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3510

7020

10530

14040

17550

<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:

0.0562

AC:

8561

AN:

152312

Hom.:

329

Cov.:

AF XY:

0.0545

AC XY:

4059

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0135

AC:

562

AN:

41582

American (AMR)

AF:

0.0357

AC:

546

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0968

AC:

336

AN:

3472

East Asian (EAS)

AF:

0.0741

AC:

384

AN:

5180

South Asian (SAS)

AF:

0.0313

AC:

151

AN:

4826

European-Finnish (FIN)

AF:

0.0658

AC:

699

AN:

10620

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0822

AC:

5588

AN:

68004

Other (OTH)

AF:

0.0497

AC:

105

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

424

848

1273

1697

2121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0755

Hom.:

152

Bravo

AF:

0.0542

Asia WGS

AF:

0.0610

AC:

214

AN:

3478

EpiCase

AF:

0.0785

EpiControl

AF:

0.0792

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 06, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.4444+4T>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant enhances the donor cite, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0624 (7579/121388 chrs tested), predominantly in individuals of European descent (0.0819; 5568/66728 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports or cited by reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Hereditary cancer-predisposing syndrome

Benign:2

May 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 02, 2018

True Health Diagnostics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 12

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLE-related polyposis and colorectal cancer syndrome

Benign:1

Jul 16, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

7.5

(source)

DANN

Benign

0.69

PhyloP100

0.30

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0060

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over