6-73500589-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_012123.4(MTO1):​c.1933C>T​(p.Arg645Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R645S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MTO1
NM_012123.4 missense

Scores

12
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.74
Variant links:
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]
EEF1A1 (HGNC:3189): (eukaryotic translation elongation factor 1 alpha 1) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas, and the other isoform (alpha 2) is expressed in brain, heart and skeletal muscle. This isoform is identified as an autoantigen in 66% of patients with Felty syndrome. This gene has been found to have multiple copies on many chromosomes, some of which, if not all, represent different pseudogenes. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-73500589-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402215.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTO1NM_012123.4 linkc.1933C>T p.Arg645Cys missense_variant Exon 12 of 12 ENST00000498286.6 NP_036255.2 Q9Y2Z2-4
MTO1NM_001123226.2 linkc.2053C>T p.Arg685Cys missense_variant Exon 13 of 13 NP_001116698.1 Q9Y2Z2-6
MTO1NM_133645.3 linkc.2008C>T p.Arg670Cys missense_variant Exon 13 of 13 NP_598400.1 Q9Y2Z2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTO1ENST00000498286.6 linkc.1933C>T p.Arg645Cys missense_variant Exon 12 of 12 1 NM_012123.4 ENSP00000419561.2 Q9Y2Z2-4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460422
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726450
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
.;.;.;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Benign
0.032
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Pathogenic
4.6
.;.;.;H
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-7.2
D;D;D;D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.68
MutPred
0.73
.;.;.;Loss of disorder (P = 0.0499);
MVP
0.82
MPC
1.0
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-74210312; API