rs143811282

chr20-17969945-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.954

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]

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]

ACMG classification

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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGME1	NM_052865.4	c.86C>G	p.Ser29Cys	missense_variant	2/5	ENST00000377710.10

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152198 Hom.: 2 Cov.: 33

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.: 4 AF XY: 0.00175 AC XY: 238 AN XY: 135910

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.: 7 Cov.: 32 AF XY: 0.000641 AC XY: 466 AN XY: 727234

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.: 2 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74486

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.: 0

Bravo AF: 0.00149

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00200 AC: 243

Asia WGS AF: 0.00635 AC: 22 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

Submissions by phenotype

not provided Benign:2

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

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
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	D
LIST_S2	Benign	0.70	T;T;T
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	0.94	D;D;N
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs143811282; hg19: chr20-17950588;