Genetic Variant MGME1:p.Thr265Ile (chr20-17988228-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052865.4(MGME1):c.794C>T(p.Thr265Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,998 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 13 hom., cov: 32)

Exomes 𝑓: 0.013 ( 151 hom. )

Consequence

MGME1
NM_052865.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.75

Publications

14 publications found

Variant links:

Genes affected

MGME1 (HGNC:16205): (mitochondrial genome maintenance exonuclease 1) The protein encoded by this gene is a nuclear-encoded mitochondrial protein necessary for the maintenance of mitochondrial genome synthesis. The encoded protein is a RecB-type exonuclease and primarily cleaves single-stranded DNA. Defects in this gene have been associated with mitochondrial DNA depletion syndrome-11. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

MGME1 links:

OVOL2 (HGNC:15804): (ovo like zinc finger 2) This gene encodes a member of the evolutionarily conserved ovo-like protein family. Mammalian members of this family contain a single zinc finger domain composed of a tetrad of C2H2 zinc fingers with variable N- and C-terminal extensions that contain intrinsically disordered domains. Members of this family are involved in epithelial development and differentiation. Knockout of this gene in mouse results in early embryonic lethality with phenotypes that include neurectoderm expansion, impaired vascularization, and heart anomalies. In humans, allelic variants of this gene have been associated with posterior polymorphous corneal dystrophy. [provided by RefSeq, Apr 2016]

OVOL2 Gene-Disease associations (from GenCC):

posterior polymorphous corneal dystrophy 1
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
congenital hereditary endothelial dystrophy type I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
posterior polymorphous corneal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

OVOL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009017646).

BP6

Variant 20-17988228-C-T is Benign according to our data. Variant chr20-17988228-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.008 (1219/152322) while in subpopulation NFE AF = 0.0141 (961/68028). AF 95% confidence interval is 0.0134. There are 13 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052865.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MGME1	NM_052865.4	MANE Select	c.794C>T	p.Thr265Ile	missense	Exon 4 of 5	NP_443097.1
MGME1	NM_001310338.2		c.839C>T	p.Thr280Ile	missense	Exon 5 of 6	NP_001297267.1
MGME1	NM_001363738.2		c.554C>T	p.Thr185Ile	missense	Exon 4 of 5	NP_001350667.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MGME1	ENST00000377710.10	TSL:1 MANE Select	c.794C>T	p.Thr265Ile	missense	Exon 4 of 5	ENSP00000366939.5
MGME1	ENST00000467391.1	TSL:1	n.377C>T		non_coding_transcript_exon	Exon 2 of 3
MGME1	ENST00000377709.1	TSL:2	c.554C>T	p.Thr185Ile	missense	Exon 4 of 5	ENSP00000366938.1

Frequencies

GnomAD3 genomes

AF:

0.00801

AC:

1219

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00318

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00745

AC:

1872

AN:

251348

AF XY:

0.00734

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00466

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.00832

GnomAD4 exome

AF:

0.0127

AC:

18580

AN:

1461676

Hom.:

151

Cov.:

AF XY:

0.0121

AC XY:

8833

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33474

American (AMR)

AF:

0.00293

AC:

131

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00117

AC:

101

AN:

86230

European-Finnish (FIN)

AF:

0.00468

AC:

250

AN:

53418

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0156

AC:

17357

AN:

1111862

Other (OTH)

AF:

0.00912

AC:

551

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

916

1833

2749

3666

4582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.00800

AC:

1219

AN:

152322

Hom.:

Cov.:

AF XY:

0.00733

AC XY:

546

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41570

American (AMR)

AF:

0.00444

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

961

AN:

68028

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0111

Hom.:

Bravo

AF:

0.00783

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00787

AC:

955

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0117

EpiControl

AF:

0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MGME1: BS1, BS2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Feb 16, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Mitochondrial DNA depletion syndrome 11

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.7

PhyloP100

7.8

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.26

Sift

Benign

0.047

Sift4G

Uncertain

0.036

Polyphen

0.95

Vest4

0.88

MVP

0.73

MPC

0.48

ClinPred

0.032

GERP RS

5.6

Varity_R

0.85

gMVP

0.71

Mutation Taster

=30/70

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over