rs143811282

Positions:

chr20-17969945-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052865.4(MGME1):c.86C>G(p.Ser29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,614,188 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 7 hom. )

Consequence

MGME1
NM_052865.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.954

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=0.007321298).

BP6

Variant 20-17969945-C-G is Benign according to our data. Variant chr20-17969945-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 235686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-17969945-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00101 (154/152318) while in subpopulation EAS AF= 0.0139 (72/5180). AF 95% confidence interval is 0.0113. There are 2 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGME1	NM_052865.4 linkuse as main transcript	c.86C>G	p.Ser29Cys	missense_variant	2/5	ENST00000377710.10	NP_443097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MGME1	ENST00000377710.10 linkuse as main transcript	c.86C>G	p.Ser29Cys	missense_variant	2/5	1	NM_052865.4	ENSP00000366939	P1
MGME1	ENST00000377709.1 linkuse as main transcript	c.86C>G	p.Ser29Cys	missense_variant	2/5	2		ENSP00000366938
MGME1	ENST00000377704.4 linkuse as main transcript	c.86C>G	p.Ser29Cys	missense_variant	2/3	3		ENSP00000366933
OVOL2	ENST00000486776.5 linkuse as main transcript	n.492-12908G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00219

AC:

551

AN:

251428

Hom.:

AF XY:

0.00175

AC XY:

238

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00761

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0119

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000693

AC:

1013

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000641

AC XY:

466

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00713

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0100

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152318

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0139

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000506

Hom.:

Bravo

AF:

0.00149

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00200

AC:

243

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2017

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. -

MGME1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;T;T

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.70

T;T;T

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.7

M;.;.

MutationTaster

Benign

0.94

D;D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.89

N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.025

D;D;D

Sift4G

Uncertain

0.044

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.25

MVP

0.69

MPC

0.086

ClinPred

0.038

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.37

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

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