dbSNP rs1241914180: MTO1:c.1260+191G>A (chr6-73480996-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_012123.4(MTO1):c.1260+191G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MTO1
NM_012123.4 intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00800

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: Uncertain_significance. The variant received 4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTO1	NM_012123.4 link	c.1260+191G>A		intron_variant	Intron 7 of 11	ENST00000498286.6	NP_036255.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6 link	c.1260+191G>A		intron_variant	Intron 7 of 11	1	NM_012123.4	ENSP00000419561.2

Frequencies

GnomAD3 genomes

AF:

0.0000400

AC:

AN:

100004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000385

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000561

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

364418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

193366

African (AFR)

AF:

0.00

AC:

AN:

9390

American (AMR)

AF:

0.00

AC:

AN:

12622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9652

East Asian (EAS)

AF:

0.00

AC:

AN:

20212

South Asian (SAS)

AF:

0.00

AC:

AN:

41026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1462

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

232634

Other (OTH)

AF:

0.00

AC:

AN:

19220

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000400

AC:

AN:

100032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

45294

show subpopulations

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

African (AFR)

AF:

0.0000384

AC:

AN:

26026

American (AMR)

AF:

0.00

AC:

AN:

6892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2918

East Asian (EAS)

AF:

0.00

AC:

AN:

3090

South Asian (SAS)

AF:

0.00

AC:

AN:

2896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000561

AC:

AN:

53464

Other (OTH)

AF:

0.00

AC:

AN:

1312

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000431883), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.288

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.74

Eigen

Benign

0.11

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.013

PhyloP100

-0.0080

GERP RS

1.4

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 5

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