chr12-132668446-A-T

Variant names:

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.2083T>A(p.Phe695Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0147 in 1,612,464 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F695L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 9 hom., cov: 32)

Exomes 𝑓: 0.015 ( 147 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 6.24

Publications

16 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), 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=0.009873003).

BP6

Variant 12-132668446-A-T is Benign according to our data. Variant chr12-132668446-A-T is described in ClinVar as Benign. ClinVar VariationId is 221179.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 = 0.0105 (1599/152248) while in subpopulation NFE AF = 0.0152 (1034/67998). AF 95% confidence interval is 0.0144. There are 9 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 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.2083T>A	p.Phe695Ile	missense	Exon 19 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.2083T>A	p.Phe695Ile	missense	Exon 19 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.2002T>A	p.Phe668Ile	missense	Exon 18 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*1130T>A		non_coding_transcript_exon	Exon 19 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1600

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0112

AC:

2795

AN:

249948

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00912

Gnomad ASJ exome

AF:

0.0193

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00678

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

AF:

0.0151

AC:

22025

AN:

1460216

Hom.:

147

Cov.:

AF XY:

0.0152

AC XY:

11070

AN XY:

726256

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

33418

American (AMR)

AF:

0.00996

AC:

443

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

533

AN:

26052

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39648

South Asian (SAS)

AF:

0.0162

AC:

1393

AN:

86012

European-Finnish (FIN)

AF:

0.00768

AC:

410

AN:

53382

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0165

AC:

18294

AN:

1111114

Other (OTH)

AF:

0.0133

AC:

804

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1157

2314

3471

4628

5785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.0105

AC:

1599

AN:

152248

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

750

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00346

AC:

144

AN:

41568

American (AMR)

AF:

0.0122

AC:

187

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.0133

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00669

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0152

AC:

1034

AN:

67998

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0131

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0160

AC:

138

ExAC

AF:

0.0108

AC:

1308

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0181

EpiControl

AF:

0.0160

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (5)

Hereditary cancer-predisposing syndrome (3)

Colorectal cancer, susceptibility to, 12 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0099

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.6

PhyloP100

6.2

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.19

Sift

Benign

0.079

Sift4G

Benign

0.10

Polyphen

0.74

Vest4

0.70

MPC

0.40

ClinPred

0.014

GERP RS

5.9

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.27

gMVP

0.81

Mutation Taster

=87/13

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