rs145043138

Positions:

chr6-73479828-A-G

Variant summary

Our verdict is Benign. Variant got -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:5

Conservation

PhyloP100: 5.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTO1	NM_012123.4 linkuse as main transcript	c.922A>G	p.Thr308Ala	missense_variant	5/12	ENST00000498286.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTO1	ENST00000498286.6 linkuse as main transcript	c.922A>G	p.Thr308Ala	missense_variant	5/12	1	NM_012123.4	P1	Q9Y2Z2-4

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

GnomAD3 exomes

AF:

0.00183

AC:

459

AN:

251218

Hom.:

AF XY:

0.00194

AC XY:

263

AN XY:

135778

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 SAS 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

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00219

Gnomad4 NFE exome

AF:

0.00358

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152318

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00341

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00288

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MTO1: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22494076) -

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2019	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP3,BS2,BS6. -

MTO1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2021

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

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

MutationTaster

Benign

0.52

D;D;D;D

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

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