ENST00000415954.6:c.1262C>G

Variant names:

• chr6-73480998-C-G
• rs1554149118
• ENST00000415954.6:c.1262C>G
• MTO1 p.Thr421Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000415954.6(MTO1):​c.1262C>G​(p.Thr421Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000936 in 106,804 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T421K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000094 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTO1 ENST00000415954.6 missense, splice_region
• Scores: Splicing: ADA: 0.02821
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.03
• Publications: 0 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14598474).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000415954.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	NM_012123.4	MANE Select	c.1260+193C>G		intron	N/A	NP_036255.2	Q9Y2Z2-4
	MTO1	NM_001123226.2		c.1262C>G	p.Thr421Arg	missense splice_region	Exon 8 of 13	NP_001116698.1	Q9Y2Z2-6
	MTO1	NM_133645.3		c.1335+193C>G		intron	N/A	NP_598400.1	Q9Y2Z2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	ENST00000415954.6	TSL:1	c.1262C>G	p.Thr421Arg	missense splice_region	Exon 8 of 13	ENSP00000402038.2	Q9Y2Z2-6
	MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1260+193C>G		intron	N/A	ENSP00000419561.2	Q9Y2Z2-4
	MTO1	ENST00000370300.8	TSL:1	c.1335+193C>G		intron	N/A	ENSP00000359323.4	Q9Y2Z2-1

Frequencies

GnomAD3 genomes AF: 0.00000936 AC: 1 AN: 106804 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000368

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 373100 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 197912

African (AFR) AF: 0.00 AC: 0 AN: 9622

American (AMR) AF: 0.00 AC: 0 AN: 12872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9858

East Asian (EAS) AF: 0.00 AC: 0 AN: 20778

South Asian (SAS) AF: 0.00 AC: 0 AN: 41778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1488

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 238498

Other (OTH) AF: 0.00 AC: 0 AN: 19682

GnomAD4 genome AF: 0.00000936 AC: 1 AN: 106804 Hom.: 0 Cov.: 23 AF XY: 0.0000207 AC XY: 1 AN XY: 48258

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

African (AFR) AF: 0.0000368 AC: 1 AN: 27154

American (AMR) AF: 0.00 AC: 0 AN: 7342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3122

East Asian (EAS) AF: 0.00 AC: 0 AN: 3294

South Asian (SAS) AF: 0.00 AC: 0 AN: 3180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57588

Other (OTH) AF: 0.00 AC: 0 AN: 1420

⚠️ 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.84
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.00097	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.0
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.025
Sift	Benign	0.10	T
Sift4G	Uncertain	0.022	D
gMVP		0.68
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.028
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1554149118;

hg19: chr6-74190721;