chr6-73500589-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_012123.4(MTO1):c.1933C>A(p.Arg645Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,612,552 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R645H) has been classified as Uncertain significance.
Frequency
Consequence
NM_012123.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTO1 | NM_012123.4 | c.1933C>A | p.Arg645Ser | missense_variant | 12/12 | ENST00000498286.6 | |
MTO1 | NM_001123226.2 | c.2053C>A | p.Arg685Ser | missense_variant | 13/13 | ||
MTO1 | NM_133645.3 | c.2008C>A | p.Arg670Ser | missense_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTO1 | ENST00000498286.6 | c.1933C>A | p.Arg645Ser | missense_variant | 12/12 | 1 | NM_012123.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000440 AC: 11AN: 249776Hom.: 0 AF XY: 0.0000593 AC XY: 8AN XY: 134958
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1460422Hom.: 1 Cov.: 30 AF XY: 0.0000454 AC XY: 33AN XY: 726450
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
Abnormal brain morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces arginine with serine at codon 645 of the MTO1 protein (p.Arg645Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs746382157, ExAC 0.02%). This missense change has been observed in individual(s) with congenital brain abnormalities (PMID: 26539891). This variant is also known as c.C2053A (p.R685S). ClinVar contains an entry for this variant (Variation ID: 402215). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 19, 2020 | This variant is associated with the following publications: (PMID: 31589614, 26539891) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at