chr20-17969868-G-A

Position:

• chr20-17969868-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_052865.4(MGME1):​c.9G>A​(p.Met3Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MGME1 NM_052865.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGME1	NM_052865.4	c.9G>A	p.Met3Ile	missense_variant	2/5	ENST00000377710.10	NP_443097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGME1	ENST00000377710.10	c.9G>A	p.Met3Ile	missense_variant	2/5	1	NM_052865.4	ENSP00000366939.5
MGME1	ENST00000377709.1	c.9G>A	p.Met3Ile	missense_variant	2/5	2		ENSP00000366938.1
MGME1	ENST00000377704.4	c.9G>A	p.Met3Ile	missense_variant	2/3	3		ENSP00000366933.4
OVOL2	ENST00000486776.5	n.492-12831C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MGME1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 3 of the MGME1 protein (p.Met3Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.50
MutPred		0.29		Gain of methylation at K4 (P = 0.0244);Gain of methylation at K4 (P = 0.0244);Gain of methylation at K4 (P = 0.0244);
MVP		0.74
MPC		0.49
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-17950511; COSMIC: COSV66623901; COSMIC: COSV66623901;