rs145843073

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_002693.3(POLG):c.1402A>G(p.Asn468Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. N468S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00083 ( 1 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:17B:1

Conservation

PhyloP100: 2.97

Publications

25 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 Gene-Disease associations (from GenCC):

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
mitochondrial DNA depletion syndrome 4a
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
autosomal dominant progressive external ophthalmoplegia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive progressive external ophthalmoplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial neurogastrointestinal encephalomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
recessive mitochondrial ataxia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
spinocerebellar ataxia with epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

POLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 3 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=0.024409533).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.1402A>G	p.Asn468Asp	missense	Exon 7 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.1402A>G	p.Asn468Asp	missense	Exon 7 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLG	ENST00000268124.11	TSL:1 MANE Select	c.1402A>G	p.Asn468Asp	missense	Exon 7 of 23	ENSP00000268124.5	P54098
POLG	ENST00000442287.6	TSL:1	c.1402A>G	p.Asn468Asp	missense	Exon 7 of 23	ENSP00000399851.2	P54098
POLG	ENST00000636937.2	TSL:5	c.1402A>G	p.Asn468Asp	missense	Exon 7 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000473

AC:

119

AN:

251488

AF XY:

0.000456

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000829

AC:

1212

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

576

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000614

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000920

AC:

1023

AN:

1112010

Other (OTH)

AF:

0.000695

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

150

225

300

375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000624

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41590

American (AMR)

AF:

0.00163

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000663

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Progressive sclerosing poliodystrophy (3)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (2)

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 (2)

Hereditary spastic paraplegia (1)

Inborn genetic diseases (1)

Lennox-Gastaut syndrome (1)

Mitochondrial disease (1)

not specified (1)

POLG-related disorder (1)

POLG-Related Spectrum Disorders (1)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1)

Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b (1)

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.20

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

M_CAP

Benign

0.075

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.95

PhyloP100

3.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.070

REVEL

Benign

0.24

Sift

Benign

0.72

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.44

MVP

0.84

MPC

0.18

ClinPred

0.0045

GERP RS

2.7

PromoterAI

0.0078

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.15

gMVP

0.22

Mutation Taster

=28/72

disease causing (ClinVar)

(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

Computational scores

Splicing

Publications

Other links and lift over