rs2307447

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.1637C>T (p.Arg546Cys) variant in POLG has been reported with an allele frequency in the African American population at 1.88% in gnomAD. (BA1). 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA292876/MONDO:0044970/014

Frequency

Genomes: 𝑓 0.0049 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 6 hom. )

Consequence

POLG
ENST00000268124.11 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 2.85

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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.1636C>T	p.Arg546Cys	missense_variant	9/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*908C>T		3_prime_UTR_variant	9/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.1636C>T	p.Arg546Cys	missense_variant	9/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.1636C>T	p.Arg546Cys	missense_variant	9/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes

AF:

0.00496

AC:

754

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00153

AC:

385

AN:

251354

Hom.:

AF XY:

0.00118

AC XY:

161

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000578

AC:

845

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

350

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0190

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00494

AC:

752

AN:

152272

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

354

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0168

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000742

Hom.:

Bravo

AF:

0.00578

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00170

AC:

206

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >1% in African population in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2019	- -

Progressive sclerosing poliodystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 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.1636C>T (NP_002684.1:p.Arg546Cys) [GRCH38: NC_000015.10:g.89326688G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:19629138 . 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). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2017

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. -

Mitochondrial disease

Benign:1

Benign, reviewed by expert panel

curation

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

May 07, 2021

The c.1637C>T (p.Arg546Cys) variant in POLG has been reported with an allele frequency in the African American population at 1.88% in gnomAD. (BA1). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

.;D

MetaRNN

Benign

0.0070

T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.030

D;D

Sift4G

Uncertain

0.053

T;T

Polyphen

0.99

D;D

Vest4

0.50

MVP

0.87

MPC

0.49

ClinPred

0.037

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.39

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