rs121434467
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The ENST00000387365.1(MT-TI):n.33A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Mitomap GenBank:
𝑓 0.0018 ( AC: 113 )
Consequence
MT-TI
ENST00000387365.1 non_coding_transcript_exon
ENST00000387365.1 non_coding_transcript_exon
Scores
Mitotip
Uncertain
Clinical Significance
MHCM-/-Maternally-inherited-hypertension-/-Maternally-inherited-deafness
Conservation
PhyloP100: 3.44
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomadMitoHomoplasmic at 167
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRNI | TRNI.1 use as main transcript | n.33A>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.33A>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 GenBank
AF:
AC:
113
Gnomad homoplasmic
AF:
AC:
167
AN:
56431
Gnomad heteroplasmic
AF:
AC:
0
AN:
56431
Alfa
AF:
Hom.:
Mitomap
MHCM-/-Maternally-inherited-hypertension-/-Maternally-inherited-deafness
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 19, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 22, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 22, 2019 | - - |
Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | 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 ). - |
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Benign:1
Benign, 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.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:
Name
Calibrated prediction
Score
Prediction
Mitotip
Uncertain
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at