Variant 20-17969871-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052865.4(MGME1):c.12G>C(p.Lys4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,455,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MGME1
NM_052865.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.46

Variant links:

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]

MGME1 links:

OVOL2 (HGNC:):

OVOL2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1680601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGME1	NM_052865.4 linkuse as main transcript	c.12G>C	p.Lys4Asn	missense_variant	2/5	ENST00000377710.10	NP_443097.1	Q9BQP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MGME1	ENST00000377710.10 linkuse as main transcript	c.12G>C	p.Lys4Asn	missense_variant	2/5	1	NM_052865.4	ENSP00000366939.5	Q9BQP7
MGME1	ENST00000377709.1 linkuse as main transcript	c.12G>C	p.Lys4Asn	missense_variant	2/5	2		ENSP00000366938.1	Q5QPE8
MGME1	ENST00000377704.4 linkuse as main transcript	c.12G>C	p.Lys4Asn	missense_variant	2/3	3		ENSP00000366933.4	Q5QPE7
OVOL2	ENST00000486776.5 linkuse as main transcript	n.492-12834C>G		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000285

AC:

AN:

245526

Hom.:

AF XY:

0.0000376

AC XY:

AN XY:

133140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000336

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1455800

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724420

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000234

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000702

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.12G>C (p.K4N) alteration is located in exon 2 (coding exon 1) of the MGME1 gene. This alteration results from a G to C substitution at nucleotide position 12, causing the lysine (K) at amino acid position 4 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;T;T

Eigen

Benign

0.019

Eigen_PC

Benign

-0.017

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.53

T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

M;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.059

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.88

P;.;.

Vest4

0.36

MutPred

0.28

Loss of methylation at K4 (P = 0.0313);Loss of methylation at K4 (P = 0.0313);Loss of methylation at K4 (P = 0.0313);

MVP

0.60

MPC

0.13

ClinPred

0.28

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over