20-17969973-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_052865.4(MGME1):c.114G>A(p.Lys38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,614,092 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: MGME1 NM_052865.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-17969973-G-A is Benign according to our data. Variant chr20-17969973-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00071 (108/152212) while in subpopulation NFE AF= 0.0011 (75/68010). AF 95% confidence interval is 0.000902. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGME1	NM_052865.4	c.114G>A	p.Lys38=	synonymous_variant	2/5	ENST00000377710.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGME1	ENST00000377710.10	c.114G>A	p.Lys38=	synonymous_variant	2/5	1	NM_052865.4	P1
MGME1	ENST00000377709.1	c.114G>A	p.Lys38=	synonymous_variant	2/5	2
MGME1	ENST00000377704.4	c.114G>A	p.Lys38=	synonymous_variant	2/3	3
OVOL2	ENST00000486776.5	n.492-12936C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000911 AC: 229 AN: 251464 Hom.: 1 AF XY: 0.000883 AC XY: 120 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00102 AC: 1487 AN: 1461880 Hom.: 3 Cov.: 32 AF XY: 0.00100 AC XY: 727 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000710 AC: 108 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000672 AC XY: 50 AN XY: 74418

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00157 Hom.: 1

Bravo AF: 0.000691

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

MGME1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.1
Dann	Benign	0.94

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: rs142670810; hg19: chr20-17950616;