rs2307441

chr15-89318595-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002693.3(POLG):c.3428A>G(p.Glu1143Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,614,076 control chromosomes in the GnomAD database, including 1,410 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. E1143Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (113 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1297 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign reviewed by expert panel B:23 O:1
• Conservation: PhyloP100: 1.90

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]

POLGARF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_002693.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.007514864).
• BP6: Variant 15-89318595-T-C is Benign according to our data. Variant chr15-89318595-T-C is described in ClinVar as [Benign]. Clinvar id is 21312.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-89318595-T-C is described in Lovd as [Likely_benign]. Variant chr15-89318595-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0265 (4035/152272) while in subpopulation NFE AF= 0.0421 (2863/68014). AF 95% confidence interval is 0.0408. There are 113 homozygotes in gnomad4. There are 1938 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 113 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.3428A>G	p.Glu1143Gly	missense_variant	21/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*2700A>G		3_prime_UTR_variant	21/23
POLG	NM_001126131.2	c.3428A>G	p.Glu1143Gly	missense_variant	21/23

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4037 AN: 152154 Hom.: 113 Cov.: 32

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

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.: 32 AF XY: 0.0379 AC XY: 27594 AN XY: 727206

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.: 32 AF XY: 0.0260 AC XY: 1938 AN XY: 74454

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: 24

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0281 AC: 3410

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:23 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

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, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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. -
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% -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Progressive sclerosing poliodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

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	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs2307441; hg19: chr15-89861826; COSMIC: COSV51520517; COSMIC: COSV51520517;