rs556539910

Variant names:

• chr20-17969930-C-T
• rs556539910
• NM_052865.4:c.71C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052865.4(MGME1):​c.71C>T​(p.Ala24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MGME1 NM_052865.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.644
• Publications: 0 publications found

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]

OVOL2 Gene-Disease associations (from GenCC):

• posterior polymorphous corneal dystrophy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital hereditary endothelial dystrophy type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• posterior polymorphous corneal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08084211).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052865.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGME1	NM_052865.4	MANE Select	c.71C>T	p.Ala24Val	missense	Exon 2 of 5	NP_443097.1	Q9BQP7
	MGME1	NM_001310338.2		c.71C>T	p.Ala24Val	missense	Exon 2 of 6	NP_001297267.1
	MGME1	NM_001363738.2		c.71C>T	p.Ala24Val	missense	Exon 2 of 5	NP_001350667.1	Q5QPE8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGME1	ENST00000377710.10	TSL:1 MANE Select	c.71C>T	p.Ala24Val	missense	Exon 2 of 5	ENSP00000366939.5	Q9BQP7
	MGME1	ENST00000948803.1		c.71C>T	p.Ala24Val	missense	Exon 1 of 5	ENSP00000618862.1
	MGME1	ENST00000895985.1		c.71C>T	p.Ala24Val	missense	Exon 1 of 5	ENSP00000566044.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.64
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.017
Sift	Benign	0.10	T
Sift4G	Uncertain	0.019	D
Polyphen		0.085	B
Vest4		0.15
MVP		0.24
MPC		0.089
ClinPred		0.13	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.082
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs556539910; hg19: chr20-17950573;