Genetic Variant MTO1:p.Thr421Lys (chr6-73480998-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000415954.6(MTO1):c.1262C>A(p.Thr421Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MTO1
ENST00000415954.6 missense, splice_region

Scores

Splicing: ADA: 0.0002478

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.03

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13732615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTO1	NM_012123.4 link	c.1260+193C>A		intron_variant	Intron 7 of 11	ENST00000498286.6	NP_036255.2	Q9Y2Z2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6 link	c.1260+193C>A		intron_variant	Intron 7 of 11	1	NM_012123.4	ENSP00000419561.2		Q9Y2Z2-4

Frequencies

GnomAD3 genomes

AF:

0.0000468

AC:

AN:

106782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000304

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000356

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000347

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000268

AC:

AN:

373098

Hom.:

Cov.:

AF XY:

0.00000505

AC XY:

AN XY:

197910

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

9622

American (AMR)

AF:

0.00

AC:

AN:

12872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9858

East Asian (EAS)

AF:

0.00

AC:

AN:

20778

South Asian (SAS)

AF:

0.0000239

AC:

AN:

41776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1488

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

238498

Other (OTH)

AF:

0.00

AC:

AN:

19682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000468

AC:

AN:

106832

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

48290

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27196

American (AMR)

AF:

0.000136

AC:

AN:

7344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3122

East Asian (EAS)

AF:

0.000305

AC:

AN:

3282

South Asian (SAS)

AF:

0.00

AC:

AN:

3180

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

2812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000347

AC:

AN:

57574

Other (OTH)

AF:

0.00

AC:

AN:

1432

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.245

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Uncertain:1

Aug 01, 2017

Phosphorus, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.34

CADD

Benign

4.8

(source)

DANN

Benign

0.72

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.43

M_CAP

Benign

0.0011

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

PhyloP100

-2.0

PROVEAN

Benign

-0.19

REVEL

Benign

0.014

Sift

Benign

0.14

Sift4G

Uncertain

0.034

Polyphen

0.55

Vest4

0.34

MutPred

0.51

Gain of ubiquitination at T421 (P = 0.0138);

MVP

0.38

MPC

0.29

ClinPred

0.21

GERP RS

0.84

gMVP

0.65

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.052

SpliceAI score (max)

0.070

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over