rs121434467
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNI | unassigned_transcript_4790 | c.33A>G | p.Ile11Met | missense_variant | Exon 1 of 1 | |||
| ND2 | unassigned_transcript_4793 | c.-175A>G | upstream_gene_variant | |||||
| TRNM | unassigned_transcript_4792 | c.-107A>G | upstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
not provided Uncertain:3
The m.4295A>G variant (rs121434467) is located at position 33 of the tRNA-isoleucine gene. Although this variant has been reported in patients with diverse symptoms including hypertrophic cardiomyopathy, encephalopathy, non-syndromic hearing loss, occipital stroke and essential hypertension, a consistent clinical presentation has not been identified (Finnila 2001, Gutierrez Cortes 2012, Li 2008, Merante 1996, Zhu 2009). Functional characterization of the variant tRNA indicates a defect in 3' processing (Levinger 2003), resulting in reduced activity of complex III in oxidative phosphorylation; however, the clinical relevance of these observations in not known (Gutierrez Cortes 2012, Merante 1996). Furthermore, the m.4295A>G variant is observed in 10 percent of individuals with the mitochondrial haplogroup K1a (87 out of 916 individual in the MITOMAP database). Therefore, based on the available information, the clinical significance of the m.4295A>G variant cannot be determined with certainty. -
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Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1
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Primary familial hypertrophic cardiomyopathy Pathogenic:1
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not specified Uncertain:1
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MTTI m.4295A>G Merante et al (1996) report the variant in two siblings with severe HCM and their mother who was phenotype negative. The proband presented at 7 months of age with cyanosis and died due to complications of HCM. Autopsy revealed proliferation of mitochondria in the heart, so the authors looked for mitochondrial variants. Notably, they did only a limited analysis of mitochondrial DNA; they sequenced tRNA genes and looked for gross deletions and duplications. The proband, who had the most severe presentation, had a >90 % heteroplasmic load in the heart, her brother had 89% variant load in the heart and developed HCM at age 4 while their mother who had a variant load of 79% in the cardiac muscle was phenotype negative for HCM but did have reduced respiratory chain activity levels. Adenosine is highly conserved at position 4295 across species. This variant has been reported in individuals from the general population: 5/2704 individuals in mtDB (www.genpath.uu.se/mtDB); 2/3735 individuals in MitoWheel (http://mitowheel.org/mitowheel.html ). -
Mitochondrial disease Uncertain:1
The m.4295A>G variant in MT-TI has been reported in at least four families from different ethnic groups with features of primary mitochondrial disease including deafness, hearing loss, and cardiomyopathy (PMIDs: 18177739, 22241583, 33398350, 34991096, 8889580; PS4_moderate). Of note, other isolated phenotypes have been reported including essential hypertension and autism spectrum disorder, but these are outside the scope of this curation (PMIDs: 11406419, 19778529, 19043581). This variant is seen in the general population (<0.5% in three large population databases: Mitomap - 112/61168, gnomAD v3.1.2 - 167/56431, and Helix - 923/195983). Notably, these occurrences are almost exclusively in haplogroup (hg) K (110/112 in specifically K1a in Mitomap; 166/167 in hg K in gnomAD, 911/923 in K in Helix) and these three databases combined reported only 15 individuals from non-K haplogroups (H, I, R, X, J, U, and V). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly benign (0.44) but HmtVAR predicts it to be pathogenic (0.75). Of note, this variant is 100% conserved among 45 species ranging from Drosophila to Homo sapiens in the extraordinarily conserved anticodon loop of tRNA Isoleucine. Cybrid studies showed multiple deleterious biochemical impacts of the variant in a Chinese family from haplogroup D4j (PMID: 33398350). Other studies showed this variant reduces the efficiency with which tRNAIle can be processed by 3′-tRNase (PMID: 18177739). An in-vitro system utilizing plasmids with tRNAIle inserts showed that this variant reduces the tRNase Z reaction 10.3-fold (PMID: 12655007). On the basis of these strong, independent, and consistent functional studies, this Expert Panel elected to give higher weight to this line of evidence (PS3_moderate). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note there was much discussion of the possible differing roles of this variant in haplogroups K1a (protective or tolerated) and D4j (damaging), however the VCEP elected to keep the classification of this variant as uncertain significance (four of 11 experts felt likely benign was the more appropriate classification). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate. -
MELAS syndrome Benign:1
The NC_012920.1:m.4295A>G variant in MT-TI gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at