12-132642993-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000320574.10(POLE):c.4555C>T(p.Arg1519Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,591,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1519L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

POLE
ENST00000320574.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.53

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032290757).

BP6

Variant 12-132642993-G-A is Benign according to our data. Variant chr12-132642993-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 413538.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000118 (18/152334) while in subpopulation SAS AF = 0.00352 (17/4830). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000320574.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.4555C>T	p.Arg1519Cys	missense	Exon 36 of 49	NP_006222.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLE	ENST00000320574.10	TSL:1 MANE Select	c.4555C>T	p.Arg1519Cys	missense	Exon 36 of 49	ENSP00000322570.5
POLE	ENST00000535270.5	TSL:1	c.4474C>T	p.Arg1492Cys	missense	Exon 35 of 48	ENSP00000445753.1
POLE	ENST00000537064.5	TSL:1	n.*4306C>T		non_coding_transcript_exon	Exon 36 of 49	ENSP00000442578.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000443

AC:

100

AN:

225934

AF XY:

0.000520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000966

Gnomad OTH exome

AF:

0.000366

GnomAD4 exome

AF:

0.000186

AC:

267

AN:

1439332

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

183

AN XY:

715172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32124

American (AMR)

AF:

0.0000265

AC:

AN:

37806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25032

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00293

AC:

243

AN:

83058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1104416

Other (OTH)

AF:

0.000185

AC:

AN:

59390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000118

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00352

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000688

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000560

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary cancer-predisposing syndrome (2)

Colorectal cancer, susceptibility to, 10 (1)

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)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.037

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

PhyloP100

4.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.27

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.94

MutPred

0.45

Gain of catalytic residue at N1521 (P = 0.0015)

MVP

0.57

MPC

0.84

ClinPred

0.16

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.46

gMVP

0.54

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over