rs118203891

Variant names:

• chrM-5874-T-C
• rs118203891
• unassigned_transcript_4798:c.18A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNY stop_lost
• Scores: Mitotip Uncertain 11
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 EXIT
• Conservation: PhyloP100: 1.61

Genes affected

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

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]

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

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

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-5874-T-C is Pathogenic according to our data. Variant chrM-5874-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9550.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNY	unassigned_transcript_4798	c.18A>G	p.Ter6Trpext*?	stop_lost	Exon 1 of 1
COX1	unassigned_transcript_4799	c.-30T>C		upstream_gene_variant
TRNN	unassigned_transcript_4796	c.-145A>G		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

EXIT

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Exercise intolerance and complex III deficiency, somatic Pathogenic:1

Oct 24, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Mitochondrial disease Uncertain:1

Jun 10, 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.5874T>C variant in MT-TY has been reported in one individual with primary mitochondrial disease to date (PMIDs: 6095966, 11071502). This woman had exercise intolerance onset in childhood, muscle weakness, ptosis, and ragged red fibers on muscle biopsy. The variant was present at 89% heteroplasmy in muscle and was absent in blood. It was also absent in blood from her healthy mother and siblings, however technology at the time would not have reliably detected presence of the variant at low heteroplasmy levels. There are no other individuals with this variant reported to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is benign (38.9 percentile) but HmtVAR predicts it to be deleterious with a score of 0.65. Single fiber testing showed higher levels of the variant in COX-negative fibers (92.3±6.7%; n=12) than in COX-positive fibers (29.9±11.8%; n=12; p<0.000001; PS3_supporting, PMID: 11071502). 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 June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. -

not provided Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203891; hg19: chrM-5875;