rs121434470
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The ENST00000387365.1(MT-TI):n.38A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-TI
ENST00000387365.1 non_coding_transcript_exon
ENST00000387365.1 non_coding_transcript_exon
Scores
Mitotip
Pathogenic
Clinical Significance
MICM
Conservation
PhyloP100: 1.74
Genes affected
MT-TI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)
MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Mitotip and hmtvar scores support pathogenic criterium.
PP5
?
Variant M-4300-A-G is Pathogenic according to our data. Variant chrM-4300-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9606.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRNI | TRNI.1 use as main transcript | n.38A>G | non_coding_transcript_exon_variant | 1/1 | |||
TRNQ | TRNQ.1 use as main transcript | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-TI | ENST00000387365.1 | n.38A>G | non_coding_transcript_exon_variant | 1/1 | |||||
MT-ND1 | ENST00000361390.2 | downstream_gene_variant | P1 | ||||||
MT-TQ | ENST00000387372.1 | downstream_gene_variant |
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
MICM
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
MERRF syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Sep 12, 2022 | The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of onset (11 months old to 40s). All cases developed hypertrophic cardiomyopathy. Muscle biopsy revealed COX negative fibers in cardiac tissue and one case had ragged red fibers in skeletal muscle. Heteroplasmy levels were predominantly the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Other affected family members did harbor the variant at 60-100%. Of note, some healthy family members had the variant ranging from 40-100% (PS4_moderate; PMIDs: 10065021, 7646516, 12767666, 12711217, 23847141). This variant segregated with disease in a family with LVH with diffuse hypertrophy as the proband's heteroplasmy was 98% in heart, 85% in muscle, and 95% in blood. His seven affected maternal relatives had heteroplasmy levels ranging from 60-92% in blood. His 12 unaffected relatives available for testing heteroplasmy ranged 50-78% in blood (PP1_moderate, PMID: 1006502). There are no reported de novo occurrences of this variant to our knowledge. There are three occurrences of this variant in Helix dataset (frequency of 0.001%) that includes two homoplasmic and one heteroplasmic individuals. This variant is absent in gnomAD v3.1.2 and in GenBank dataset therefore the frequency is still low enough to meet criteria for 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 pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PP1_moderate. - |
Primary dilated cardiomyopathy;C0205700:Asymmetric septal hypertrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2018 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 21, 2003 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Mitotip
Pathogenic
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at