chrM-4284-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PS3_SupportingPP1
This summary comes from the ClinGen Evidence Repository: The m.4284G>A variant in MT-TI has been reported in one family to date (PMID:11782991). The proband had isolated spastic paraparesis and normal muscle biopsy including normal respiratory chain enzyme activities. The variant was present at 55% muscle, 50% in hair, 40% in urine, 30% in skin, 20% in buccal, and 20% in blood. His mother had truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, and diabetes. Her brain MRI showed cortical and subcortical diffuse atrophy and muscle biopsy showed reduced activities of complex I and complex IV. The variant was present at 80% in muscle, 20% in urine, and 30% in blood. The proband had one brother with a multisystem progressive disorder who ultimately died of cardiomyopathy. His brain imaging showed marked cortical and subcortical atrophy. His muscle biopsy showed reductions in complex I, complex IV, and complex V. The variant was present at 90% in muscle. As this is the only family reported to date, PS4 could not be applied. The proband had another brother who was healthy and had undetectable levels of the variant in blood and urine. Therefore, this variant segregated with disease in multiple affected family members and a healthy family member had undetectable levels of the variant (PP1; PMID:11782991). In silico predictions are inconsistent as MitoTIP suggests this variant is benign (35th percentile) and HmtVAR predicts it to be deleterious (0.55). This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.003%; Helix's 195,983 sequences: AF=0.001%; and gnomAD v3.1.2: AF=0.007% as this is homoplasmic in four individuals and heteroplasmic in two individual). Given the frequency of this variant, it does not meet PM2 criterion. Cybrid studies showed that the homoplasmic mutant clones had decreases in COX activity and oxygen consumption rates compared to controls (PS3_supporting, PMID:11782991). 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 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120571/MONDO:0044970/015
Frequency
Consequence
ENST00000387365.1 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNI | TRNI.1 use as main transcript | n.22G>A | 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 | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TI | ENST00000387365.1 | n.22G>A | non_coding_transcript_exon_variant | 1/1 | ||||||
| MT-ND1 | ENST00000361390.2 | downstream_gene_variant | ENSP00000354687 | P1 | ||||||
| MT-TQ | ENST00000387372.1 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
MERRF syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
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.4284G>A variant in MT-TI 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: PM8, PM9, PM10 - |
Multisystem disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Mitochondrial disease Uncertain:1
| Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Nov 28, 2023 | The m.4284G>A variant in MT-TI has been reported in one family to date (PMID: 11782991). The proband had isolated spastic paraparesis and normal muscle biopsy including normal respiratory chain enzyme activities. The variant was present at 55% muscle, 50% in hair, 40% in urine, 30% in skin, 20% in buccal, and 20% in blood. His mother had truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, and diabetes. Her brain MRI showed cortical and subcortical diffuse atrophy and muscle biopsy showed reduced activities of complex I and complex IV. The variant was present at 80% in muscle, 20% in urine, and 30% in blood. The proband had one brother with a multisystem progressive disorder who ultimately died of cardiomyopathy. His brain imaging showed marked cortical and subcortical atrophy. His muscle biopsy showed reductions in complex I, complex IV, and complex V. The variant was present at 90% in muscle. As this is the only family reported to date, PS4 could not be applied. The proband had another brother who was healthy and had undetectable levels of the variant in blood and urine. Therefore, this variant segregated with disease in multiple affected family members and a healthy family member had undetectable levels of the variant (PP1; PMID: 11782991). In silico predictions are inconsistent as MitoTIP suggests this variant is benign (35th percentile) and HmtVAR predicts it to be deleterious (0.55). This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.003%; Helix's 195,983 sequences: AF=0.001%; and gnomAD v3.1.2: AF=0.007% as this is homoplasmic in four individuals and heteroplasmic in two individual). Given the frequency of this variant, it does not meet PM2 criterion. Cybrid studies showed that the homoplasmic mutant clones had decreases in COX activity and oxygen consumption rates compared to controls (PS3_supporting, PMID: 11782991). 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 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 07, 2021 | The variant has 0.000106 frequency in the gnomAD(v3) database (56,426 total allele number, 4 homoplasmic alleles, 2 heteroplasmic alleles). The m.4284G>A variant has been reported as likely pathogenic in ClinVar [variation ID: 9604, variant also described in PMID:31965079]. Given the low level of heteroplasmy in detected here, the lack of information on heteroplasmy levels of this variant in different tissues of this proband and its inheritance from a reportedly unaffected mother, the m.4284G>A variant identified in the mitochondrial genome is reported as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at