NM_002693.3:c.125G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_002693.3(POLG):c.125G>A(p.Arg42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,423,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R42W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.461

Publications

8 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029483706).

BP6

Variant 15-89333630-C-T is Benign according to our data. Variant chr15-89333630-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206476.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLG	NM_002693.3	MANE Select	c.125G>A	p.Arg42Gln	missense	Exon 2 of 23	NP_002684.1
POLGARF	NM_001430120.1	MANE Select	c.180G>A	p.Ala60Ala	synonymous	Exon 1 of 2	NP_001417049.1
POLG	NM_001126131.2		c.125G>A	p.Arg42Gln	missense	Exon 2 of 23	NP_001119603.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLG	ENST00000268124.11	TSL:1 MANE Select	c.125G>A	p.Arg42Gln	missense	Exon 2 of 23	ENSP00000268124.5
POLG	ENST00000442287.6	TSL:1	c.125G>A	p.Arg42Gln	missense	Exon 2 of 23	ENSP00000399851.2
POLGARF	ENST00000706918.1	MANE Select	c.180G>A	p.Ala60Ala	synonymous	Exon 1 of 2	ENSP00000516626.1

Frequencies

GnomAD3 genomes

AF:

0.0000574

AC:

AN:

139254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000979

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000626

Gnomad OTH

AF:

0.000527

GnomAD2 exomes

AF:

0.000131

AC:

AN:

206784

AF XY:

0.0000699

show subpopulations

Gnomad AFR exome

AF:

0.000623

Gnomad AMR exome

AF:

0.000159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000201

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.000189

GnomAD4 exome

AF:

0.0000304

AC:

AN:

1284364

Hom.:

Cov.:

AF XY:

0.0000328

AC XY:

AN XY:

640702

show subpopulations

African (AFR)

AF:

0.0000378

AC:

AN:

26440

American (AMR)

AF:

0.000122

AC:

AN:

40898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24008

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38644

South Asian (SAS)

AF:

0.0000374

AC:

AN:

80240

European-Finnish (FIN)

AF:

0.000229

AC:

AN:

43640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5190

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

970990

Other (OTH)

AF:

0.0000184

AC:

AN:

54314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.401

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000574

AC:

AN:

139254

Hom.:

Cov.:

AF XY:

0.0000734

AC XY:

AN XY:

68138

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

34802

American (AMR)

AF:

0.000139

AC:

AN:

14360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3284

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4506

European-Finnish (FIN)

AF:

0.0000979

AC:

AN:

10218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000626

AC:

AN:

63862

Other (OTH)

AF:

0.000527

AC:

AN:

1896

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000184

Hom.:

ExAC

AF:

0.000232

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia (1)

POLG-related disorder (1)

Progressive sclerosing poliodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

8.3

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.21

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.0

PhyloP100

-0.46

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.020

REVEL

Uncertain

0.32

Sift

Benign

0.48

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.15

MVP

0.59

MPC

0.18

ClinPred

0.0046

GERP RS

-0.80

PromoterAI

0.0076

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.20

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over