20-17969902-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_052865.4(MGME1):c.43A>T(p.Ser15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,380 control chromosomes in the GnomAD database, including 11,807 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S15N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 862 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10945 hom. )

Consequence

MGME1
NM_052865.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.680

Publications

28 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=0.0016505718).

BP6

Variant 20-17969902-A-T is Benign according to our data. Variant chr20-17969902-A-T is described in ClinVar as Benign. ClinVar VariationId is 380041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGME1	NM_052865.4 link	c.43A>T	p.Ser15Cys	missense_variant	Exon 2 of 5	ENST00000377710.10	NP_443097.1	Q9BQP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGME1	ENST00000377710.10 link	c.43A>T	p.Ser15Cys	missense_variant	Exon 2 of 5	1	NM_052865.4	ENSP00000366939.5		Q9BQP7

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15233

AN:

152140

Hom.:

861

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0746

Gnomad AMI

AF:

0.0604

Gnomad AMR

AF:

0.0942

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.0321

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0689

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.111

GnomAD2 exomes

AF:

0.102

AC:

25471

AN:

250600

AF XY:

0.107

show subpopulations

Gnomad AFR exome

AF:

0.0735

Gnomad AMR exome

AF:

0.0634

Gnomad ASJ exome

AF:

0.0920

Gnomad EAS exome

AF:

0.0366

Gnomad FIN exome

AF:

0.0707

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.119

AC:

174276

AN:

1461122

Hom.:

10945

Cov.:

AF XY:

0.120

AC XY:

87320

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.0760

AC:

2539

AN:

33396

American (AMR)

AF:

0.0680

AC:

3024

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.0972

AC:

2538

AN:

26108

East Asian (EAS)

AF:

0.0332

AC:

1318

AN:

39700

South Asian (SAS)

AF:

0.129

AC:

11157

AN:

86184

European-Finnish (FIN)

AF:

0.0722

AC:

3856

AN:

53414

Middle Eastern (MID)

AF:

0.181

AC:

1040

AN:

5754

European-Non Finnish (NFE)

AF:

0.127

AC:

141504

AN:

1111718

Other (OTH)

AF:

0.121

AC:

7300

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

8314

16627

24941

33254

41568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5072

10144

15216

20288

25360

<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:

0.100

AC:

15230

AN:

152258

Hom.:

862

Cov.:

AF XY:

0.0973

AC XY:

7243

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0745

AC:

3095

AN:

41534

American (AMR)

AF:

0.0940

AC:

1438

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3470

East Asian (EAS)

AF:

0.0320

AC:

166

AN:

5190

South Asian (SAS)

AF:

0.124

AC:

597

AN:

4830

European-Finnish (FIN)

AF:

0.0689

AC:

731

AN:

10614

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.125

AC:

8516

AN:

68014

Other (OTH)

AF:

0.110

AC:

232

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

694

1388

2081

2775

3469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.121

Hom.:

882

Bravo

AF:

0.102

TwinsUK

AF:

0.132

AC:

490

ALSPAC

AF:

0.119

AC:

459

ESP6500AA

AF:

0.0710

AC:

313

ESP6500EA

AF:

0.131

AC:

1129

ExAC

AF:

0.104

AC:

12575

Asia WGS

AF:

0.0800

AC:

277

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.136

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 16, 2015

GeneDx

Significance: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

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.019

T;T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

0.68

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.021

D;D;D

Sift4G

Uncertain

0.035

D;D;T

Polyphen

0.98

D;.;.

Vest4

0.18

MPC

0.28

ClinPred

0.020

GERP RS

-0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.092

gMVP

0.077

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over