rs200217371

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.Arg666Ter) 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

Genomes: 𝑓 0.00034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

MTO1
NM_012123.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.06

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 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0399 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000335 (51/152232) while in subpopulation AMR AF= 0.00255 (39/15278). AF 95% confidence interval is 0.00192. There are 1 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MTO1	NM_012123.4 linkuse as main transcript	c.1996C>T	p.Arg666Ter	stop_gained	12/12	ENST00000498286.6
MTO1	NM_001123226.2 linkuse as main transcript	c.2116C>T	p.Arg706Ter	stop_gained	13/13
MTO1	NM_133645.3 linkuse as main transcript	c.2071C>T	p.Arg691Ter	stop_gained	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTO1	ENST00000498286.6 linkuse as main transcript	c.1996C>T	p.Arg666Ter	stop_gained	12/12	1	NM_012123.4	P1	Q9Y2Z2-4

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

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:

0.000118

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251212

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461574

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000335

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.000567

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	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

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 13, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.29

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.41

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.25

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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