rs5744941

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.4444+4T>A variant causes a splice donor 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. 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_donor_region, intron

Scores

Splicing: ADA: 0.00002649

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.304

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 ClinVar 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 Lovd as [Benign].

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/exons	MANE	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.4444+4T>A		splice_donor_region_variant, intron_variant		ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.4444+4T>A		splice_donor_region_variant, intron_variant		1	NM_006231.4	P1

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

GnomAD3 exomes

AF:

0.0624

AC:

15693

AN:

251402

Hom.:

585

AF XY:

0.0631

AC XY:

8567

AN XY:

135876

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 SAS exome

AF:

0.0306

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

Gnomad4 AFR exome

AF:

0.0117

Gnomad4 AMR exome

AF:

0.0308

Gnomad4 ASJ exome

AF:

0.0952

Gnomad4 EAS exome

AF:

0.0798

Gnomad4 SAS exome

AF:

0.0316

Gnomad4 FIN exome

AF:

0.0666

Gnomad4 NFE exome

AF:

0.0862

Gnomad4 OTH exome

AF:

0.0780

GnomAD4 genome

AF:

0.0562

AC:

8561

AN:

152312

Hom.:

329

Cov.:

AF XY:

0.0545

AC XY:

4059

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0135

Gnomad4 AMR

AF:

0.0357

Gnomad4 ASJ

AF:

0.0968

Gnomad4 EAS

AF:

0.0741

Gnomad4 SAS

AF:

0.0313

Gnomad4 FIN

AF:

0.0658

Gnomad4 NFE

AF:

0.0822

Gnomad4 OTH

AF:

0.0497

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Mar 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 19, 2015	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. -

Colorectal cancer, susceptibility to, 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

Cadd

Benign

7.5

Dann

Benign

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over