20-17988228-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_052865.4(MGME1):c.794C>T(p.Thr265Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,998 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (13 hom., cov: 32)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: MGME1 NM_052865.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.75

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009017646).
• BP6: Variant 20-17988228-C-T is Benign according to our data. Variant chr20-17988228-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-17988228-C-T is described in Lovd as [Benign]. Variant chr20-17988228-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.008 (1219/152322) while in subpopulation NFE AF= 0.0141 (961/68028). AF 95% confidence interval is 0.0134. There are 13 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGME1	NM_052865.4	c.794C>T	p.Thr265Ile	missense_variant	4/5	ENST00000377710.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGME1	ENST00000377710.10	c.794C>T	p.Thr265Ile	missense_variant	4/5	1	NM_052865.4	P1

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1219 AN: 152204 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00745 AC: 1872 AN: 251348 Hom.: 15 AF XY: 0.00734 AC XY: 997 AN XY: 135848

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.0127 AC: 18580 AN: 1461676 Hom.: 151 Cov.: 30 AF XY: 0.0121 AC XY: 8833 AN XY: 727148

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00468

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.00912

GnomAD4 genome AF: 0.00800 AC: 1219 AN: 152322 Hom.: 13 Cov.: 32 AF XY: 0.00733 AC XY: 546 AN XY: 74490

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0113 Hom.: 24

Bravo AF: 0.00783

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00787 AC: 955

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MGME1: BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial DNA depletion syndrome 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Benign	0.26
Sift	Benign	0.047	D;T
Sift4G	Uncertain	0.036	D;D
Polyphen		0.95	P;.
Vest4		0.88
MVP		0.73
MPC		0.48
ClinPred		0.032	T
GERP RS		5.6
Varity_R		0.85
gMVP		0.71

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: rs76599088; hg19: chr20-17968871; COSMIC: COSV99071250;