rs2307441

Positions:

chr15-89318595-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BA1BS2

This summary comes from the ClinGen Evidence Repository: The c.3428 A>G (p.E1143G) variant in POLG has been reported 2.881 % in gnomAD (BA1). It is also seen in the homozygous state in 175 individuals in gnomAD and 65 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248706/MONDO:0044970/014

Frequency

Genomes: 𝑓 0.026 ( 113 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1297 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:24O:1

Conservation

PhyloP100: 1.90

Variant links:

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLG links:

POLGARF (HGNC:):

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.3428A>G	p.Glu1143Gly	missense_variant	21/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2700A>G		3_prime_UTR_variant	21/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.3428A>G	p.Glu1143Gly	missense_variant	21/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3428A>G	p.Glu1143Gly	missense_variant	21/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4037

AN:

152154

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00598

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0614

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0342

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0287

AC:

7222

AN:

251414

Hom.:

156

AF XY:

0.0293

AC XY:

3984

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0603

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0176

Gnomad FIN exome

AF:

0.0317

Gnomad NFE exome

AF:

0.0416

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0383

AC:

56044

AN:

1461804

Hom.:

1297

Cov.:

AF XY:

0.0379

AC XY:

27594

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00409

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.0636

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0177

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0432

Gnomad4 OTH exome

AF:

0.0386

GnomAD4 genome

AF:

0.0265

AC:

4035

AN:

152272

Hom.:

113

Cov.:

AF XY:

0.0260

AC XY:

1938

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00597

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0614

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.0342

Gnomad4 NFE

AF:

0.0421

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0393

Hom.:

264

Bravo

AF:

0.0243

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0413

AC:

159

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0388

AC:

334

ExAC

AF:

0.0281

AC:

3410

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0411

EpiControl

AF:

0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:24Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2022	Variant summary: POLG c.3428A>G (p.Glu1143Gly) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.029 in 251414 control chromosomes in the gnomAD database, including 156 homozygotes, strongly suggesting that the variant is benign. c.3428A>G has been reported in the literature in cis with a pathogenic variant in individuals affected with POLG-Related Spectrum Disorders, indicating that it is likely benign and not the cause of the disease phenotype (e.g. Ferrari_2005, Horvath_2006). At least one publication reports experimental evidence evaluating an impact on protein function and the results showed no damaging effect of this variant on polymerase activity (e.g. Chan_2006). Thirteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All classified the variant as either benign (n= 9) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 37/2178=1.6% -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17980715, 21686371, 25497598, 23448099, 17088268, 22166854, 23783014, 20691285, 20981092, 21228398, 15477547, 27884173, 26104464, 26468652, 18991199, 24122062, 30255931, 25925909, 25462018, 33469851) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2018	- -

Progressive sclerosing poliodystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.3428A>G (NP_002684.1:p.Glu1143Gly) [GRCH38: NC_000015.10:g.89318595T>C] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 03, 2021

- -

POLG-Related Spectrum Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

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. -

Fanconi anemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mitochondrial disease

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

May 06, 2021

The c.3428A>G (p.E1143G) variant in POLG has been reported 2.881 % in gnomAD (BA1). It is also seen in the homozygous state in 175 individuals in gnomAD and 65 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 29, 2021

- -

Association with valproate-induced liver toxicity

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Variant interpreted as Risk factor and reported on 09-22-2017 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Benign

0.12

Eigen_PC

Benign

0.087

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

.;D

MetaRNN

Benign

0.0075

T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

0.96

D;D

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.58

Sift

Benign

0.038

D;D

Sift4G

Benign

0.16

T;T

Polyphen

0.81

P;P

Vest4

0.15

MPC

0.18

ClinPred

0.030

GERP RS

1.5

Varity_R

0.24

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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