20-17969924-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_052865.4(MGME1):​c.65C>A​(p.Ser22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MGME1
NM_052865.4 stop_gained

Scores

1
2
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.570
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-17969924-C-A is Pathogenic according to our data. Variant chr20-17969924-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2165318.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MGME1NM_052865.4 linkuse as main transcriptc.65C>A p.Ser22* stop_gained 2/5 ENST00000377710.10 NP_443097.1 Q9BQP7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MGME1ENST00000377710.10 linkuse as main transcriptc.65C>A p.Ser22* stop_gained 2/51 NM_052865.4 ENSP00000366939.5 Q9BQP7
MGME1ENST00000377709.1 linkuse as main transcriptc.65C>A p.Ser22* stop_gained 2/52 ENSP00000366938.1 Q5QPE8
MGME1ENST00000377704.4 linkuse as main transcriptc.65C>A p.Ser22* stop_gained 2/33 ENSP00000366933.4 Q5QPE7
OVOL2ENST00000486776.5 linkuse as main transcriptn.492-12887G>T intron_variant 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461768
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 06, 2023This sequence change creates a premature translational stop signal (p.Ser22*) in the MGME1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MGME1 are known to be pathogenic (PMID: 23313956). This variant is present in population databases (rs761126029, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MGME1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
32
DANN
Uncertain
0.98
Eigen
Benign
0.056
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.12
N
Vest4
0.083
GERP RS
2.3

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

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

Other links and lift over

dbSNP: rs761126029; hg19: chr20-17950567; API