M-5702-A-G

Variant names:

• chrM-5702-A-G
• rs1603220093
• unassigned_transcript_4796:c.28T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNN synonymous
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 4.79

Genes affected

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

COX1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

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]

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNN	unassigned_transcript_4796	c.28T>C	p.Leu10Leu	synonymous_variant	Exon 1 of 1
COX1	unassigned_transcript_4799	c.-202A>G		upstream_gene_variant
TRNA	unassigned_transcript_4795	c.-47T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Ptosis;C0162292:External ophthalmoplegia Pathogenic:1

Jan 24, 2020

Mitochondrial Disorders Lab i+12, Hospital Universitario 12 de Octubre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The m.5702A>G variant in the MT-TN gene (mtDNA, tRNA-Asn) is a novel variant. The variant was absent in the polymorphisms and pathogenic mutations databases of MITOMAP. Evidences supporting the pathogenicity of the variant are: i) skeletal muscle heteroplasmy (65%), ii) the nucleotide change involves the 28U:42A pair in the "anticodon stem" of the mitochondrial tRNA-Asn structure, predicting a Watson-Crick C:A mismatch. Family segregation studies showed absence of the variant in the blood and uroepithelial cells from the proband's asymptomatic mother, and four asymptomatic siblings. -

Mitochondrial disease Uncertain:1

Sep 24, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.5702A>G variant in MT-TN has been reported in one individual with primary mitochondrial disease to date (PMID: 32161153; this appears to be the same individual reported in an abstract, https://www.nmd-journal.com/article/S0960-8966(16)30622-8/abstract, and included in the ClinVar submission for this variant). Clinical features in this woman include ophthalmoplegia, ptosis, myopathy, and ragged red and COX-negative fibers on muscle biopsy. The variant is present in the proband at 60% heteroplasmy muscle, 10% in urine, and absent in blood and skin fibroblasts. The variant is absent in blood and urine from her mother and four asymptomatic siblings (PM6_supporting; https://www.nmd-journal.com/article/S0960-8966(16)30622-8/abstract). There are no additional individuals or families reported with de novo occurrences of this variant or with this variant segregating with clinical manifestations to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 73.9%; HmtVAR: 0.05). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Benign	0.050

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603220093; hg19: chrM-5703;