rs73155056

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006231.4(POLE):c.6763A>T(p.Ile2255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,582 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2255M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0048 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 34 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.266

Publications

5 publications found

Variant links:

COSMIC-nc: COSV104629482

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), Genomics England PanelApp, 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 (MetaRNN=0.002878487).

BP6

Variant 12-132624795-T-A is Benign according to our data. Variant chr12-132624795-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00485 (738/152290) while in subpopulation NFE AF = 0.00538 (366/68020). AF 95% confidence interval is 0.00493. There are 6 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

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.6763A>T	p.Ile2255Phe	missense	Exon 49 of 49	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.6763A>T	p.Ile2255Phe	missense	Exon 49 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.6682A>T	p.Ile2228Phe	missense	Exon 48 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*6514A>T		non_coding_transcript_exon	Exon 49 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.00485

AC:

738

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00469

AC:

1175

AN:

250552

AF XY:

0.00451

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00418

AC:

6100

AN:

1460292

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

2955

AN XY:

726564

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

33438

American (AMR)

AF:

0.00148

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000510

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0249

AC:

1331

AN:

53408

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00393

AC:

4363

AN:

1110564

Other (OTH)

AF:

0.00340

AC:

205

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

334

668

1001

1335

1669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00485

AC:

738

AN:

152290

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

441

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41548

American (AMR)

AF:

0.00314

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0265

AC:

281

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00538

AC:

366

AN:

68020

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00418

Hom.:

Bravo

AF:

0.00249

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00432

AC:

525

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00314

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (7)

Colorectal cancer, susceptibility to, 12 (2)

Hereditary cancer-predisposing syndrome (2)

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.23

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

PhyloP100

0.27

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

REVEL

Benign

0.12

Sift

Benign

0.062

Sift4G

Benign

0.071

Polyphen

0.022

Vest4

0.44

MVP

0.24

MPC

0.32

ClinPred

0.010

GERP RS

2.5

Varity_R

0.28

gMVP

0.70

Mutation Taster

=61/39

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

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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