M-4450-G-A

Position:

• chrM-4450-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000387377.1(MT-TM):​n.49G>A variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TM ENST00000387377.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 Myopathy-/-MELAS-/-Leigh-Syndrome-/-EXIT
• Conservation: PhyloP100: 6.32

Genes affected

MT-TM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNM (HGNC:):

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-TQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-4450-G-A is Pathogenic according to our data. Variant chrM-4450-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986440.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNM	TRNM.1	n.49G>A		non_coding_transcript_exon_variant	1/1
TRNQ	TRNQ.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TM	ENST00000387377.1	n.49G>A		non_coding_transcript_exon_variant	1/1
MT-ND2	ENST00000361453.3			upstream_gene_variant				P1
MT-TQ	ENST00000387372.1			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Myopathy-/-MELAS-/-Leigh-Syndrome-/-EXIT

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Feb 27, 2023

The m.4450G>A variant in MT-TM has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). The first individual reported was a girl with childhood onset myopathy (fatigue, proximal muscle weakness, exercise intolerance) and developmental delay. Muscle biopsy revealed COX-negative fibers and a combined respiratory chain enzyme deficiency. The variant was present at 67% in muscle, 10% in fibroblasts, and was undetectable in blood and buccal samples (PMID: 25468263). The variant was undetectable in her healthy mother’s blood, muscle, and urinary sediment (PS2_moderate). The second individual reported was a girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and the variant was present at varying levels (20-59%) in several tissues tested. Fibroblasts in this individual showed reduced oxygen consumption and reduced activities of respiratory chain complexes I and IV (PMID: 30739820). There are no other large families reported in the medical literature to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic (83.7 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed high heteroplasmy levels in ragged blue fibers (94% ± 5.4%) and variant was not detected in normal appearing fibers (PMID: 25468263, PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 27, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS2_moderate, PM2_supporting, PP3, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrM-4451;