12-132649503-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006231.4(POLE):c.3808G>T(p.Val1270Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. V1270I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.81

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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029839128).

BP6

Variant 12-132649503-C-A is Benign according to our data. Variant chr12-132649503-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3422156.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.3808G>T	p.Val1270Phe	missense_variant	Exon 31 of 49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.3808G>T	p.Val1270Phe	missense_variant	Exon 31 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000809

AC:

189

AN:

233676

AF XY:

0.000716

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.000997

Gnomad ASJ exome

AF:

0.000733

Gnomad EAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.000690

Gnomad OTH exome

AF:

0.000693

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000128

AC:

186

AN:

1454088

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

723218

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000602

AC:

AN:

33214

American (AMR)

AF:

0.00127

AC:

AN:

43352

Ashkenazi Jewish (ASJ)

AF:

0.000116

AC:

AN:

25872

East Asian (EAS)

AF:

0.00179

AC:

AN:

39146

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85924

European-Finnish (FIN)

AF:

0.000533

AC:

AN:

50648

Middle Eastern (MID)

AF:

0.000189

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1110554

Other (OTH)

AF:

0.0000666

AC:

AN:

60094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.255

Heterozygous variant carriers

122

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

Cov.:

Alfa

AF:

0.0000572

Hom.:

ExAC

AF:

0.00256

AC:

311

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:1

Oct 28, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

4.8

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.15

Sift

Benign

0.048

D;D

Sift4G

Uncertain

0.040

D;D

Polyphen

0.63

P;P

Vest4

0.70

MVP

0.58

MPC

0.31

ClinPred

0.037

GERP RS

5.7

Varity_R

0.40

gMVP

0.63

Mutation Taster

=79/21

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over