rs118203886

Variant names:

• chrM-611-G-A
• rs118203886
• unassigned_transcript_4784:c.35G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000000000(TRNF):​c.35G>A​(p.Trp12*) variant causes a stop gained change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNF ENST00000000000 stop_gained
• Scores: Mitotip Uncertain 13
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 MERRF
• Conservation: PhyloP100: 9.15
• Publications: 2 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 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-611-G-A is Pathogenic according to our data. Variant chrM-611-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9574.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387314.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TF	ENST00000387314.1	TSL:6	n.35G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR1	ENST00000389680.2	TSL:6	n.-37G>A		upstream_gene	N/A

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MERRF

Status: Reported

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

MERRF syndrome Pathogenic:1 Other:1

Sep 25, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification 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.611G>A variant in MT-TF has been reported in one individual with primary mitochondrial disease (PMID: 15184630). This individual had a clinical diagnosis of myoclonic epilepsy with ragged red fibers (MERRF) characterized by progressive myoclonus, migraines, exercise intolerance, imbalance, memory impairment, progressive sensorineural hearing loss, restricted upgaze, and short stature. Muscle biopsy showed ragged red and COX-deficient fibers. The variant was present at 91% in skeletal muscle and was undetectable in blood, buccal cells, and urinary sediment. The variant was not detected in blood, buccal cells, or urinary sediment from the mother, brother, and daughter. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). MitoTIP predicts the variant is possibly pathogenic (51.2 percentile) and HmtVAR predicts the variant is pathogenic (score of 0.85, PP3). Single fiber testing showed higher levels of the variant in COX-negative ragged red fibers (93.3 ± 4%, n=10) than in COX-positive non-ragged red fibers (17.4 ± 7.3%, n=10, PMID: 15184630). Furthermore, additional functional studies showed a decrease in aminoacylation activity compared to wild type (PMID: 17878308; PS3_moderate). 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): PM2_supporting, PP3, PS3_moderate.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	0.85
PhyloP100		9.1

Other links and lift over

dbSNP: rs118203886; hg19: chrM-613;