rs139449947
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_012123.4(MTO1):c.1480G>A(p.Gly494Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,612,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
MTO1
NM_012123.4 missense
NM_012123.4 missense
Scores
6
7
4
Clinical Significance
Conservation
PhyloP100: 5.03
Genes affected
MTO1 (HGNC:19261): (mitochondrial tRNA translation optimization 1) This gene encodes a mitochondrial protein thought to be involved in mitochondrial tRNA modification. The encoded protein may also play a role in the expression of the non-syndromic and aminoglycoside-induced deafness phenotypes associated with a specific mutation in the mitochondrial 12S rRNA gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTO1 | NM_012123.4 | c.1480G>A | p.Gly494Ser | missense_variant | 9/12 | ENST00000498286.6 | |
MTO1 | NM_001123226.2 | c.1600G>A | p.Gly534Ser | missense_variant | 10/13 | ||
MTO1 | NM_133645.3 | c.1555G>A | p.Gly519Ser | missense_variant | 10/13 | ||
MTO1 | XM_047418605.1 | c.1275G>A | p.Leu425= | synonymous_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTO1 | ENST00000498286.6 | c.1480G>A | p.Gly494Ser | missense_variant | 9/12 | 1 | NM_012123.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000959 AC: 24AN: 250290Hom.: 0 AF XY: 0.0000886 AC XY: 12AN XY: 135392
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GnomAD4 exome AF: 0.000131 AC: 192AN: 1460244Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93AN XY: 726470
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74442
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2022 | The c.1600G>A (p.G534S) alteration is located in exon 10 (coding exon 10) of the MTO1 gene. This alteration results from a G to A substitution at nucleotide position 1600, causing the glycine (G) at amino acid position 534 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 494 of the MTO1 protein (p.Gly494Ser). This variant is present in population databases (rs139449947, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MTO1-related conditions. ClinVar contains an entry for this variant (Variation ID: 569553). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTO1 protein function. 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 | Nov 07, 2022 | Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
T;D;D;D;D
Polyphen
D;D;.;D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at