M-9997-T-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP5_Strong
The ENST00000387429.1(MT-TG):n.7T>A 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-TG
ENST00000387429.1 non_coding_transcript_exon
ENST00000387429.1 non_coding_transcript_exon
Scores
Mitotip
Pathogenic
Clinical Significance
Unspecified-patient-from-clinical-lab,MHCM
Conservation
PhyloP100: 1.32
Genes affected
MT-TG (HGNC:7486): (mitochondrially encoded tRNA glycine)
MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
No frequency data in Mitomap. Probably very rare.
PP5
Variant M-9997-T-A is Pathogenic according to our data. Variant chrM-9997-T-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 690090.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRNG | TRNG.1 use as main transcript | n.7T>A | non_coding_transcript_exon_variant | 1/1 | ||||
COX3 | COX3.1 use as main transcript | downstream_gene_variant | YP_003024032.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MT-TG | ENST00000387429.1 | n.7T>A | non_coding_transcript_exon_variant | 1/1 | ||||||
MT-CO3 | ENST00000362079.2 | downstream_gene_variant | ENSP00000354982 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
Unspecified-patient-from-clinical-lab,MHCM
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jul 12, 2019 | The NC_012920.1:m.9997T>A variant in MT-TG gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PM5, PM7, PM9, PM10 - |
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jul 22, 2024 | The m.9997T>A variant in MT-TG has been reported in one individual to date, however clinical details were not provided (PMID: 31965079). Similarly, there is no available information on segregation in family members or de novo status. It is possible this individual was reported in a poster abstract submitted by Roggenbuck et al., 2016 (https://www.neurology.org/doi/10.1212/WNL.86.16_supplement.P5.016), but this has not been confirmed. The individual reported with this variant in this abstract was a man with exercise intolerance, myalgia, muscle weakness, ptosis, neuropathy, dilated cardiomyopathy, and renal disease. Respiratory chain enzyme testing on muscle showed low cytochrome c oxidase activity but exact values were not provided. The variant was reported to be present at homoplasmy in the proband and was also reported in other maternal family members with varying clinical features, however details were not provided. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is deleterious (95.2 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (PP3). 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 July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Mitotip
Pathogenic
Hmtvar
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at