rs115109291

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_002693.3(POLG):c.408C>G(p.Asp136Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,568,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D136Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 1.66

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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, 13 uncertain in NM_002693.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009656161).

BP6

Variant 15-89333347-G-C is Benign according to our data. Variant chr15-89333347-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206576.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLG	NM_002693.3 linkuse as main transcript	c.408C>G	p.Asp136Glu	missense_variant	2/23	ENST00000268124.11
POLGARF	NM_001406557.1 linkuse as main transcript	c.463C>G	p.Pro155Ala	missense_variant	2/23
POLG	NM_001126131.2 linkuse as main transcript	c.408C>G	p.Asp136Glu	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.408C>G	p.Asp136Glu	missense_variant	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1 linkuse as main transcript	c.463C>G	p.Pro155Ala	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes

AF:

0.000755

AC:

115

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

176174

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

96018

show subpopulations

Gnomad AFR exome

AF:

0.00361

Gnomad AMR exome

AF:

0.0000721

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000209

GnomAD4 exome

AF:

0.0000833

AC:

118

AN:

1415842

Hom.:

Cov.:

AF XY:

0.0000699

AC XY:

AN XY:

701130

show subpopulations

Gnomad4 AFR exome

AF:

0.00316

Gnomad4 AMR exome

AF:

0.000129

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.000761

AC:

116

AN:

152370

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.00279

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000869

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000176

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	Observed as heterozygous in two siblings with epilepsy and was considered by the authors to be a variant of unknown clinical significance (Blok et al., 2009).; This variant is associated with the following publications: (PMID: 24508722, 21880868, 19578034) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2023	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2018	- -

Progressive sclerosing poliodystrophy

Benign:2

Likely 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.408C>G (NP_002684.1:p.Asp136Glu) [GRCH38: NC_000015.10:g.89333347G>C] variant in POLG gene is interpretated to be a Likely 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). 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 Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

The p.D136E variant (also known as c.408C>G), located in coding exon 1 of the POLG gene, results from a C to G substitution at nucleotide position 408. The aspartic acid at codon 136 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in two brothers with epilepsy who had p.Q45R on the other chromosome; the variant was not found in 100 control individuals (Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

POLG-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.88

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.080

N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.43

B;B

Vest4

0.35

MutPred

0.42

Gain of disorder (P = 0.2129);Gain of disorder (P = 0.2129);

MVP

0.88

MPC

0.16

ClinPred

0.014

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.51

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