rs786200951

Positions:

• chrM-5610-G-A

Variant summary

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

The ENST00000387392.1(MT-TA):​n.46C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TA ENST00000387392.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 11
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Myopathy
• Conservation: PhyloP100: 1.26

Genes affected

MT-TA (HGNC:7475): (mitochondrially encoded tRNA alanine)

TRNA (HGNC:):

MT-TW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

MT-TN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNA	TRNA.1	n.46C>T		non_coding_transcript_exon_variant	1/1
TRNN	TRNN.1			downstream_gene_variant
TRNW	TRNW.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TA	ENST00000387392.1	n.46C>T		non_coding_transcript_exon_variant	1/1
MT-TW	ENST00000387382.1			downstream_gene_variant
MT-TN	ENST00000387400.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Myopathy

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Inborn mitochondrial myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Dec 15, 2014

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Feb 12, 2024

The m.5610G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease to date, in a 69-year-old woman with progressive limb girdle muscle weakness, dysarthria, and myopathic facies. Ragged red fibers and COX-negative fibers were noted on muscle biopsy. The variant was present at 91% heteroplasmy in muscle and 87% heteroplasmy in blood (PMID: 25873012). The variant was present at lower (9-26% heteroplasmy) to undetectable levels in healthy family members although this expert panel notes some of these family members were not yet the age of the proband when she began to experience symptoms (PP1; PMID: 25873012). There are no reported de novo occurrences of this variant to our knowledge. 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 (98%; n=20) than in COX-positive fibers (78%; n=21, P = 0.0002; PS3_supporting, PMID: 25873012). Additionally, studies have shown decreased steady-state levels of tRNA Alanine in muscle from the proband (PMID: 25873012). Computational predictors are discordant as MitoTIP suggests this variant is benign (38.7 percentile) and HmtVAR predicts it to be pathogenic (0.55). Of note, this variant is highly conserved among primates at 83%. 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 February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PM2_supporting, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200951; hg19: chrM-5611;