NM_052865.4:c.7A>C

Variant names:

• chr20-17969866-A-C
• rs771609402
• NM_052865.4:c.7A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052865.4(MGME1):​c.7A>C​(p.Met3Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,452,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MGME1 NM_052865.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37635508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGME1	NM_052865.4	c.7A>C	p.Met3Leu	missense_variant	Exon 2 of 5	ENST00000377710.10	NP_443097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGME1	ENST00000377710.10	c.7A>C	p.Met3Leu	missense_variant	Exon 2 of 5	1	NM_052865.4	ENSP00000366939.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000824 AC: 2 AN: 242626 Hom.: 0 AF XY: 0.00000760 AC XY: 1 AN XY: 131658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452288 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.089	T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.071	T;T;D
Polyphen		0.98	D;.;.
Vest4		0.49
MutPred		0.25		Gain of methylation at K4 (P = 0.0345);Gain of methylation at K4 (P = 0.0345);Gain of methylation at K4 (P = 0.0345);
MVP		0.73
MPC		0.45
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.24

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: rs771609402; hg19: chr20-17950509;