rs145043138

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012123.4(MTO1):c.922A>G(p.Thr308Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00281 in 1,613,106 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T308M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 8 hom. )

Consequence

MTO1
NM_012123.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 5.99

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

MTO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011800498).

BP6

Variant 6-73479828-A-G is Benign according to our data. Variant chr6-73479828-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00187 (285/152318) while in subpopulation NFE AF = 0.00341 (232/68034). AF 95% confidence interval is 0.00305. There are 0 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTO1	NM_012123.4 link	c.922A>G	p.Thr308Ala	missense_variant	Exon 5 of 12	ENST00000498286.6	NP_036255.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6 link	c.922A>G	p.Thr308Ala	missense_variant	Exon 5 of 12	1	NM_012123.4	ENSP00000419561.2

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

285

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00183

AC:

459

AN:

251218

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00332

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00290

AC:

4240

AN:

1460788

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

2054

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33448

American (AMR)

AF:

0.000201

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00219

AC:

117

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00358

AC:

3978

AN:

1111086

Other (OTH)

AF:

0.00202

AC:

122

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

199

398

597

796

995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152318

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41576

American (AMR)

AF:

0.000981

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00341

AC:

232

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00285

Hom.:

Bravo

AF:

0.00168

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00183

AC:

222

EpiCase

AF:

0.00311

EpiControl

AF:

0.00255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22494076) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MTO1: BS2 -

Mar 14, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP3,BS2,BS6. -

Dec 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

MTO1-related disorder

Benign:1

Apr 09, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

.;.;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.0

M;M;.;M

PhyloP100

6.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.036

D;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.73

P;P;.;P

Vest4

0.30

MVP

0.78

MPC

0.82

ClinPred

0.021

GERP RS

4.3

Varity_R

0.085

gMVP

0.45

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over