20-17969912-TTTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_Supporting BS1_Supporting

The NM_052865.4(MGME1):c.55_57del(p.Ser19del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,856 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (2 hom.)
• Consequence: MGME1 NM_052865.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.55

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 Uncertain_significance. Variant got 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_052865.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000065 (95/1461544) while in subpopulation MID AF= 0.00486 (28/5760). AF 95% confidence interval is 0.00345. There are 2 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGME1	NM_052865.4	c.55_57del	p.Ser19del	inframe_deletion	2/5	ENST00000377710.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGME1	ENST00000377710.10	c.55_57del	p.Ser19del	inframe_deletion	2/5	1	NM_052865.4	P1
MGME1	ENST00000377704.4	c.55_57del	p.Ser19del	inframe_deletion	2/3	3
MGME1	ENST00000377709.1	c.55_57del	p.Ser19del	inframe_deletion	2/5	2
OVOL2	ENST00000486776.5	n.492-12878_492-12876del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250894 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461544 Hom.: 2 AF XY: 0.0000784 AC XY: 57 AN XY: 727116

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000718

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 01, 2020

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM2,PM4,PM3_Supportin -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2022

This variant, c.55_57del, results in the deletion of 1 amino acid(s) of the MGME1 protein (p.Ser19del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766468409, gnomAD 0.01%). This variant has been observed in individual(s) with mitochondrial depletion syndrome (PMID: 28097321). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 984721). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs766468409; hg19: chr20-17950555;