chr6-73500652-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BS1_Supporting
The NM_012123.4(MTO1):c.1996C>T(p.Arg666*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,613,806 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_012123.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MTO1 | NM_012123.4 | c.1996C>T | p.Arg666* | stop_gained | Exon 12 of 12 | ENST00000498286.6 | NP_036255.2 | |
MTO1 | NM_001123226.2 | c.2116C>T | p.Arg706* | stop_gained | Exon 13 of 13 | NP_001116698.1 | ||
MTO1 | NM_133645.3 | c.2071C>T | p.Arg691* | stop_gained | Exon 13 of 13 | NP_598400.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152114Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251212Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135756
GnomAD4 exome AF: 0.0000876 AC: 128AN: 1461574Hom.: 0 Cov.: 30 AF XY: 0.0000784 AC XY: 57AN XY: 727086
GnomAD4 genome AF: 0.000335 AC: 51AN: 152232Hom.: 1 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74428
ClinVar
Submissions by phenotype
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency Uncertain:2
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This sequence change creates a premature translational stop signal (p.Arg666*) in the MTO1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the MTO1 protein. This variant is present in population databases (rs200217371, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of MTO1-related conditions (PMID: 27151179). ClinVar contains an entry for this variant (Variation ID: 547882). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Variant summary: MTO1 c.1996C>T (p.Arg666X) results in a premature termination codon in a region where nonsense mediated decay is not predicted to occur. This was validated experimentally where nonsense mediated decay was found to be absent in fibroblasts derived from a patient homozygous for this variant (Kramer_2016). The premature termination is predicted to remove the last 27 amino acids of the encoded protein, including 3 amino acids located at the end of the tRNA uridine 5-carboxymethylaminomethyl modification enzyme MnmG, C-terminal domain (IPR026904). The variant allele was found at a frequency of 0.00011 in 251212 control chromosomes (gnomAD). c.1996C>T has been reported in the literature in one homozygous individual affected with liver complex III defect (Kramer_2016), however this individual was also homozygous for a different variant that was functionally determined to be the cause of their phenotype (LYRM7 c.52delA, p.Arg18AspfsX12). Two ClinVar submitters have assessed this variant since 2014: both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and/or functional importance become available. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at