15-89333627-T-C

Position:

chr15-89333627-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002693.3(POLG):c.128A>G(p.Gln43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,580,742 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 34 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 51 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -6.18

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:

POLGARF (HGNC:):

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030815005).

BP6

Variant 15-89333627-T-C is Benign according to our data. Variant chr15-89333627-T-C is described in ClinVar as [Benign]. Clinvar id is 129989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2169/151788) while in subpopulation AFR AF= 0.0412 (1708/41428). AF 95% confidence interval is 0.0396. There are 34 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3 linkuse as main transcript	c.128A>G	p.Gln43Arg	missense_variant	2/23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 linkuse as main transcript	c.128A>G	p.Gln43Arg	missense_variant	2/23		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001406557.1 linkuse as main transcript	c.183A>G	p.Ala61Ala	synonymous_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.128A>G	p.Gln43Arg	missense_variant	2/23	1	NM_002693.3	ENSP00000268124.5		P54098
POLGARF	ENST00000706918.1 linkuse as main transcript	c.183A>G	p.Ala61Ala	synonymous_variant	1/2			ENSP00000516626.1		A0A3B3IS91

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2151

AN:

151676

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0409

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00526

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00618

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00114

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.00523

AC:

1057

AN:

202064

Hom.:

AF XY:

0.00487

AC XY:

544

AN XY:

111630

show subpopulations

Gnomad AFR exome

AF:

0.0343

Gnomad AMR exome

AF:

0.00342

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00475

Gnomad SAS exome

AF:

0.00533

Gnomad FIN exome

AF:

0.00103

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00475

GnomAD4 exome

AF:

0.00443

AC:

6336

AN:

1428954

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3098

AN XY:

709510

show subpopulations

Gnomad4 AFR exome

AF:

0.0425

Gnomad4 AMR exome

AF:

0.00391

Gnomad4 ASJ exome

AF:

0.00580

Gnomad4 EAS exome

AF:

0.00308

Gnomad4 SAS exome

AF:

0.00587

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00312

Gnomad4 OTH exome

AF:

0.00825

GnomAD4 genome

AF:

0.0143

AC:

2169

AN:

151788

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

998

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.0412

Gnomad4 AMR

AF:

0.00525

Gnomad4 ASJ

AF:

0.00577

Gnomad4 EAS

AF:

0.00619

Gnomad4 SAS

AF:

0.00623

Gnomad4 FIN

AF:

0.00114

Gnomad4 NFE

AF:

0.00363

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00868

Hom.:

Bravo

AF:

0.0161

ExAC

AF:

0.00511

AC:

580

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2013	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2014	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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.128A>G (NP_002684.1:p.Gln43Arg) [GRCH38: NC_000015.10:g.89333627T>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. BA1:Minor allele frequency is too high for the Mitochondrial DNA depletion syndrome 4A (Alpers type). 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	- -

POLG-Related Spectrum Disorders

Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 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. -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

1.1

DANN

Benign

0.081

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.29

.;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.19

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.34

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0

B;B

Vest4

0.11

MVP

0.52

MPC

0.16

ClinPred

0.014

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.053

gMVP

0.12

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