rs121434476
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
TRNG
missense
missense
Scores
Mitotip
Pathogenic
Clinical Significance
PEM
Conservation
PhyloP100: 7.62
Genes affected
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ACMG classification
Classification made for transcript
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 |
---|---|---|---|---|---|---|---|---|
TRNG | unassigned_transcript_4808 use as main transcript | c.20T>C | p.Val7Ala | missense_variant | 1/1 | |||
ND3 | unassigned_transcript_4809 use as main transcript | c.-49T>C | upstream_gene_variant | |||||
COX3 | unassigned_transcript_4807 use as main transcript | c.*20T>C | downstream_gene_variant | |||||
use as main transcript |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|
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
PEM
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Exercise intolerance Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 23, 2002 | - - |
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Nov 14, 2022 | The m.10010T>C variant in MT-TG has been reported in six unrelated individuals with primary mitochondrial disease. Features in affected individuals include Leigh syndrome (in two individuals), lactic acidosis, hyperCKemia, developmental delay, exercise intolerance, seizures, ataxia, sensorineural hearing loss, and optic atrophy. Muscle biopsies revealed ragged red fibers, COX-deficient fibers, and reduced activities of complexes I, III, and IV. The heteroplasmy levels of the variant in affected individuals ranged from 5.4% in blood to 92% in muscle. In cases that had more than one tissue tested, the heteroplasmy level was consistently and significantly higher in muscle (PS4_moderate; PMIDs: 26469001, 11971101, 16120360, 23847141, 9199564). There are no reported de novo occurrences of this variant to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing in two separate individuals showed higher levels of the variant in COX-negative fibers (97.3% and 91.7%) than in COX-positive fibers (87.2% and 58%) (PS3_supporting, PMIDs: 9199564, 11971101). The computational predictor MitoTIP suggests this variant is pathogenic (82.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (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 November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_supporting, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Mitotip
Pathogenic
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at