Variant 12-132659414-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006231.4(POLE):c.3156G>A(p.Thr1052=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,613,846 control chromosomes in the GnomAD database, including 179,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23133 hom., cov: 33)

Exomes 𝑓: 0.46 ( 156015 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 12-132659414-C-T is Benign according to our data. Variant chr12-132659414-C-T is described in ClinVar as [Benign]. Clinvar id is 380212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132659414-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.3156G>A	p.Thr1052=	synonymous_variant	26/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.3156G>A	p.Thr1052=	synonymous_variant	26/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.535

AC:

81396

AN:

152042

Hom.:

23086

Cov.:

show subpopulations

Gnomad AFR

AF:

0.715

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.383

Gnomad EAS

AF:

0.701

Gnomad SAS

AF:

0.558

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.528

GnomAD3 exomes

AF:

0.503

AC:

126545

AN:

251400

Hom.:

33325

AF XY:

0.496

AC XY:

67383

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.716

Gnomad AMR exome

AF:

0.578

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.705

Gnomad SAS exome

AF:

0.548

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.431

Gnomad OTH exome

AF:

0.476

GnomAD4 exome

AF:

0.457

AC:

667281

AN:

1461686

Hom.:

156015

Cov.:

AF XY:

0.459

AC XY:

333403

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.716

Gnomad4 AMR exome

AF:

0.572

Gnomad4 ASJ exome

AF:

0.390

Gnomad4 EAS exome

AF:

0.697

Gnomad4 SAS exome

AF:

0.546

Gnomad4 FIN exome

AF:

0.427

Gnomad4 NFE exome

AF:

0.430

Gnomad4 OTH exome

AF:

0.471

GnomAD4 genome

AF:

0.536

AC:

81493

AN:

152160

Hom.:

23133

Cov.:

AF XY:

0.537

AC XY:

39967

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.715

Gnomad4 AMR

AF:

0.555

Gnomad4 ASJ

AF:

0.383

Gnomad4 EAS

AF:

0.701

Gnomad4 SAS

AF:

0.558

Gnomad4 FIN

AF:

0.433

Gnomad4 NFE

AF:

0.434

Gnomad4 OTH

AF:

0.531

Alfa

AF:

0.456

Hom.:

20978

Bravo

AF:

0.551

Asia WGS

AF:

0.590

AC:

2050

AN:

3478

EpiCase

AF:

0.433

EpiControl

AF:

0.430

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2016	Variant summary: The POLE c.3156G>A (p.Thr1052Thr) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 9827/18014 control chromosomes at a frequency of 0.5455202 (with numerous hozomygotes occurrence), which significantly exceeds the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. This variant has been reported in patients and classified by authors as polymorphism. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Colorectal cancer, susceptibility to, 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2015

This alteration is classified as 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. -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.9

DANN

Benign

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over