M-590-A-G

Position:

• chrM-590-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000387314.1(MT-TF):​n.14A>G variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TF ENST00000387314.1 non_coding_transcript_exon
• Scores: Mitotip Benign 5.9
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 EXIT+ataxia+RP
• Conservation: PhyloP100: 8.18

Genes affected

MT-TF (HGNC:7481): (mitochondrially encoded tRNA phenylalanine)

TRNF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• BP4: Mitotip and hmtvar scores support benign criterium.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNF	TRNF.1	n.14A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TF	ENST00000387314.1	n.14A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56433

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56433

Mitomap

EXIT+ataxia+RP

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Jun 24, 2024	The m.590A>G variant in MT-TF has been reported in one individual to date, in a woman with childhood onset mitochondrial myopathy. She had exercise intolerance, cerebellar ataxia, and retinitis pigmentosa. Muscle biopsy showed many ragged red fibers, 60% COX-negative fibers, and lipid overload. Respiratory chain enzyme activities were normal. The variant was present at 92% in muscle and was undetectable in blood, urine, and buccal sample. Haplogroup was H80 (PMID: 32419253). The variant was present at <5% in blood from her healthy mother and was undetectable in mother’s urine and buccal sample, and was undetectable in blood, buccal sample, and urine from her healthy sister. This cannot be considered evidence of de novo status as the variant was also undetectable in the proband’s blood. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (89.10±9.3%; N = at least 10) than in COX-positive fibers (44.74±24.79%; N = at least 10), p<0.0001 (PS3_supporting, PMID: 32419253). The computational predictor MitoTIP suggests this variant is neutral (16.3 percentile) and HmtVAR predicts it to be polymorphic with a score of 0.05. 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 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. -
Pathogenic, no assertion criteria provided	in vitro	Medical Genetics, CHU Nice	Oct 01, 2019	Static cerebellar ataxia, exercise intolerance, retinitis pigmentosa -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	5.9
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: rs2068676854; hg19: chrM-592;