20-17969902-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052865.4(MGME1):c.43A>T(p.Ser15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,380 control chromosomes in the GnomAD database, including 11,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S15N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (862 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10945 hom.)
• Consequence: MGME1 NM_052865.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.680

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=0.0016505718).
• BP6: Variant 20-17969902-A-T is Benign according to our data. Variant chr20-17969902-A-T is described in ClinVar as [Benign]. Clinvar id is 380041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGME1	NM_052865.4	c.43A>T	p.Ser15Cys	missense_variant	2/5	ENST00000377710.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGME1	ENST00000377710.10	c.43A>T	p.Ser15Cys	missense_variant	2/5	1	NM_052865.4	P1
MGME1	ENST00000377709.1	c.43A>T	p.Ser15Cys	missense_variant	2/5	2
MGME1	ENST00000377704.4	c.43A>T	p.Ser15Cys	missense_variant	2/3	3
OVOL2	ENST00000486776.5	n.492-12865T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15233 AN: 152140 Hom.: 861 Cov.: 33

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0942

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.102 AC: 25471 AN: 250600 Hom.: 1483 AF XY: 0.107 AC XY: 14564 AN XY: 135606

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.0634

Gnomad ASJ exome AF: 0.0920

Gnomad EAS exome AF: 0.0366

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.0707

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.119 AC: 174276 AN: 1461122 Hom.: 10945 Cov.: 32 AF XY: 0.120 AC XY: 87320 AN XY: 726930

Gnomad4 AFR exome AF: 0.0760

Gnomad4 AMR exome AF: 0.0680

Gnomad4 ASJ exome AF: 0.0972

Gnomad4 EAS exome AF: 0.0332

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.0722

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.100 AC: 15230 AN: 152258 Hom.: 862 Cov.: 33 AF XY: 0.0973 AC XY: 7243 AN XY: 74454

Gnomad4 AFR AF: 0.0745

Gnomad4 AMR AF: 0.0940

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.0320

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0689

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.110

Alfa AF: 0.121 Hom.: 882

Bravo AF: 0.102

TwinsUK AF: 0.132 AC: 490

ALSPAC AF: 0.119 AC: 459

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.131 AC: 1129

ExAC AF: 0.104 AC: 12575

Asia WGS AF: 0.0800 AC: 277 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2015

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.035	D;D;T
Polyphen		0.98	D;.;.
Vest4		0.18
MPC		0.28
ClinPred		0.020	T
GERP RS		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11551768; hg19: chr20-17950545; COSMIC: COSV66624187; COSMIC: COSV66624187;