20-17969860-A-G

Variant names:

• chr20-17969860-A-G
• rs778604585
• NM_052865.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PVS1_Supporting

The NM_052865.4(MGME1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,448,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MGME1 NM_052865.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.707
• 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 1 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 codons. Genomic position: 17969866. Lost 0.007 part of the original CDS.

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.1A>G	p.Met1?	start_lost	Exon 2 of 5	NP_443097.1	Q9BQP7
	MGME1	NM_001310338.2		c.1A>G	p.Met1?	start_lost	Exon 2 of 6	NP_001297267.1
	MGME1	NM_001363738.2		c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 2 of 5	ENSP00000366939.5	Q9BQP7
	MGME1	ENST00000948803.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENSP00000618862.1
	MGME1	ENST00000895985.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENSP00000566044.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000208 AC: 5 AN: 239940 AF XY: 0.0000384

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1448992 Hom.: 0 Cov.: 31 AF XY: 0.0000166 AC XY: 12 AN XY: 720752

African (AFR) AF: 0.00 AC: 0 AN: 32554

American (AMR) AF: 0.00 AC: 0 AN: 41072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25268

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.000177 AC: 15 AN: 84536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107450

Other (OTH) AF: 0.00 AC: 0 AN: 59748

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.76
DANN	Benign	0.89
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0052	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.99	T
PhyloP100		-0.71
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.26
Sift	Benign	0.086	T
Sift4G	Uncertain	0.039	D
Polyphen		0.0010	B
Vest4		0.14
MutPred		1.0		Gain of methylation at K2 (P = 0.0449)
MVP		0.20
ClinPred		0.064	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.11
Mutation Taster		=170/30	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: rs778604585; hg19: chr20-17950503;