rs387906734

Variant names:

• chrM-586-G-A
• rs387906734
• unassigned_transcript_4784:c.10G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000000000(TRNF):​c.10G>A​(p.Ala4Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNF ENST00000000000 missense
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 Extrapyramidal-disorder-with-akinesia-rigidity+-psychosis-and-SNHL
• Conservation: PhyloP100: 8.79
• Publications: 1 publications found

Genes affected

TRNF (HGNC:7481): (mitochondrially encoded tRNA phenylalanine)

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNF	unassigned_transcript_4784	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 1
RNR1	unassigned_transcript_4785	n.-62G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TF	ENST00000387314.1	n.10G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-RNR1	ENST00000389680.2	n.-62G>A		upstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Disease(s): Extrapyramidal-disorder-with-akinesia-rigidity+-psychosis-and-SNHL

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.586G>A variant in MT-TF gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PM8, PM9 -

Mitochondrial encephalopathy Pathogenic:1

Nov 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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.586G>A variant in MT-TF has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 21060018, 31463198). One individual was a 57-year-old woman with hearing loss onset in her mid 40s that progressed to profound hearing loss in her 50s, myopathy and progressive exercise intolerance with reduced mobility and falls onset in her late 40s, and spasticity, facial grimacing, dementia, and psychiatric manifestations in her mid 50s (PMID: 21060018). Brain imaging showed generalized cerebral, cerebellar, and brainstem atrophy. Cerebrospinal fluid lactate was elevated. Muscle biopsy showed ragged red fibers and COX-deficient fibers. The variant was present in muscle at 85% heteroplasmy, urinary epithelia at 29%, and blood at 3%. Her mother had died however DNA from paraffin-embedded breast tissue was obtained and revealed the variant at 13% heteroplasmy. The other individual was a 14-year-old boy with exercise intolerance and muscle weakness that followed a stable course (PMID: 31463198). Brain imaging was normal. Lactate was elevated in blood. Muscle biopsy showed ragged red fibers, COX-negative fibers, and mitochondrial respiratory chain complexes I, III, and IV deficiency. The variant was present at >90% in muscle, 40% in urinary epithelia, and was present at trace levels in blood. The variant was undetectable in his mother’s blood and urinary epithelia (PM6_supporting; PMID: 31463198). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (89.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (99.4±0.2%, n=11) than in COX-positive fibers (72.1±8.5%, n=9; p<0.001; PS3_supporting, PMID: 21060018). 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): PS4_supporting, PM6_supporting, PP3, PS3_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.60
PhyloP100		8.8

Other links and lift over

dbSNP: rs387906734; hg19: chrM-588;