rs786200950

Positions:

• chrM-5631-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNA synonymous
• Scores: Mitotip Uncertain 12
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 Myopathy
• Conservation: PhyloP100: 0.504

Genes affected

TRNA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-5631-G-A is Pathogenic according to our data. Variant chrM-5631-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 162369.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNA	unassigned_transcript_4796	c.25C>T	p.Leu9Leu	synonymous_variant	1/1
TRNN	unassigned_transcript_4797	c.*26C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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 GenBank AF: 0.0 AC: 1

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56424

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56424

Mitomap

Myopathy

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Feb 26, 2024	The m.5631G>A in MT-TA has been reported in one individual to date, in a woman with adult-onset myopathy (PMID: 25873012). Her muscle biopsy showed numerous COX-deficient fibers and ragged red fibers. Decreased activities of mitochondrial respiratory chain enzymes complexes I, II/III, and IV were noted although values were not provided. The variant was present in the proband at 92% in muscle, 77% in blood, 77% in hair shafts, 69% in urinary epithelial cells, and 44% in buccal sample. As this is the only case reported to date, PS4 could not be applied. Her healthy mother had the variant present at lower heteroplasmy levels (8% blood, 4% urine, 6% buccal sample) however, given no additional family members were tested, segregation evidence (PP1) could not be applied. There are no reported de novo occurrences of this variant to our knowledge. Computational predictors are conflicting precluding consideration of PP3 or BP4 (MitoTIP: 43.4%; HmtVAR: 0.45). There is one occurrence of this variant in Mitomap's 61, 134 sequences (AF=0.002%; Hg L0a); one heteroplasmic occurrence in Helix's 195,983 sequences (AF=0.001%; 10-20% heteroplasmy, Hg W); and one heteroplasmic occurrence in gnomAD v3.1.2 (0.002%; Hg V, PM2_supporting). Single fiber testing showed higher levels of the variant in COX deficient fibers (n=18; 95.1% +/- 0.45) than in COX positive fibers (n=22; 83.8% +/- 3.38; PS3_supporting, PMID: 25873012). 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 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting. -

Inborn mitochondrial myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Dec 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200950; hg19: chrM-5632; COSMIC: COSV104419786;