chr6-73500589-C-A

Variant names:

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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 1 hom. )

Consequence

MTO1
NM_012123.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

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]

MTO1 links:

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]

EEF1A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

PP5

Variant 6-73500589-C-A is Pathogenic according to our data. 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}. Variant chr6-73500589-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTO1	NM_012123.4 link	c.1933C>A	p.Arg645Ser	missense_variant	Exon 12 of 12	ENST00000498286.6	NP_036255.2	Q9Y2Z2-4
MTO1	NM_001123226.2 link	c.2053C>A	p.Arg685Ser	missense_variant	Exon 13 of 13		NP_001116698.1	Q9Y2Z2-6
MTO1	NM_133645.3 link	c.2008C>A	p.Arg670Ser	missense_variant	Exon 13 of 13		NP_598400.1	Q9Y2Z2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6 link	c.1933C>A	p.Arg645Ser	missense_variant	Exon 12 of 12	1	NM_012123.4	ENSP00000419561.2		Q9Y2Z2-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

249776

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

134958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000264

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1460422

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

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:

0.000419

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Uncertain:1

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 645 of the MTO1 protein (p.Arg645Ser). This variant is present in population databases (rs746382157, gnomAD 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). 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

Aug 19, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31589614, 26539891) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;.;.;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

4.0

.;.;.;H

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.2

D;D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.014

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.76

MutPred

0.70

.;.;.;Gain of glycosylation at R670 (P = 0.0221);

MVP

0.88

MPC

0.94

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over