rs5744886

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.3379-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,613,706 control chromosomes in the GnomAD database, including 1,214 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 0.026 ( 146 hom., cov: 32)

Exomes 𝑓: 0.027 ( 1068 hom. )

Consequence

POLE
NM_006231.4 splice_region, intron

Scores

Splicing: ADA: 0.0004335

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.264

Publications

3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
facial dysmorphism-immunodeficiency-livedo-short stature syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
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

new If you want to explore the variant's impact on the transcript NM_006231.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.8).

BP6

Variant 12-132657434-A-G is Benign according to our data. Variant chr12-132657434-A-G is described in ClinVar as Benign. ClinVar VariationId is 380222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.3379-5T>C		splice_region intron	N/A	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.3379-5T>C	splice_region intron	N/A	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.3298-5T>C	splice_region intron	N/A	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*3130-5T>C	splice_region intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.0263

AC:

4009

AN:

152146

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00591

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0241

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0382

AC:

9593

AN:

250962

AF XY:

0.0331

show subpopulations

Gnomad AFR exome

AF:

0.00591

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.00686

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0307

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0323

GnomAD4 exome

AF:

0.0267

AC:

38990

AN:

1461442

Hom.:

1068

Cov.:

AF XY:

0.0256

AC XY:

18601

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00421

AC:

141

AN:

33470

American (AMR)

AF:

0.156

AC:

6987

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00685

AC:

179

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.00730

AC:

629

AN:

86210

European-Finnish (FIN)

AF:

0.0312

AC:

1669

AN:

53410

Middle Eastern (MID)

AF:

0.00315

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0252

AC:

28002

AN:

1111744

Other (OTH)

AF:

0.0225

AC:

1361

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1825

3649

5474

7298

9123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1126

2252

3378

4504

5630

<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:

0.0264

AC:

4025

AN:

152264

Hom.:

146

Cov.:

AF XY:

0.0283

AC XY:

2104

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00590

AC:

245

AN:

41558

American (AMR)

AF:

0.109

AC:

1661

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0313

AC:

332

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0241

AC:

1639

AN:

68008

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

189

378

566

755

944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0224

Hom.:

Bravo

AF:

0.0301

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0202

EpiControl

AF:

0.0224

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Colorectal cancer, susceptibility to, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.6

(source)

DANN

Benign

0.49

PhyloP100

0.26

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00043

dbscSNV1_RF

Benign

0.036

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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