Genetic Variant ENST00000415954.6:c.1262C>A (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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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