rs11551768

Positions:

chr20-17969902-A-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 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=0.0016505718).

BP6

Variant 20-17969902-A-T is Benign according to our data. Variant chr20-17969902-A-T is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
MGME1	NM_052865.4 linkuse as main transcript	c.43A>T	p.Ser15Cys	missense_variant	2/5	ENST00000377710.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MGME1	ENST00000377710.10 linkuse as main transcript	c.43A>T	p.Ser15Cys	missense_variant	2/5	1	NM_052865.4	P1
MGME1	ENST00000377709.1 linkuse as main transcript	c.43A>T	p.Ser15Cys	missense_variant	2/5	2
MGME1	ENST00000377704.4 linkuse as main transcript	c.43A>T	p.Ser15Cys	missense_variant	2/3	3
OVOL2	ENST00000486776.5 linkuse as main transcript	n.492-12865T>A		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes

AF:

0.102

AC:

25471

AN:

250600

Hom.:

1483

AF XY:

0.107

AC XY:

14564

AN XY:

135606

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 SAS exome

AF:

0.131

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

Gnomad4 AFR exome

AF:

0.0760

Gnomad4 AMR exome

AF:

0.0680

Gnomad4 ASJ exome

AF:

0.0972

Gnomad4 EAS exome

AF:

0.0332

Gnomad4 SAS exome

AF:

0.129

Gnomad4 FIN exome

AF:

0.0722

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.100

AC:

15230

AN:

152258

Hom.:

862

Cov.:

AF XY:

0.0973

AC XY:

7243

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0745

Gnomad4 AMR

AF:

0.0940

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.0320

Gnomad4 SAS

AF:

0.124

Gnomad4 FIN

AF:

0.0689

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.110

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2015

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

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;.;.

MutationTaster

Benign

1.0

N;N;N

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

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

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