ENST00000415954.6:c.1262C>A

Variant names:

• chr6-73480998-C-A
• rs1554149118
• ENST00000415954.6:c.1262C>A
• MTO1 p.Thr421Lys

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13732615).

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>A		intron	N/A	NP_036255.2	Q9Y2Z2-4
	MTO1	NM_001123226.2		c.1262C>A	p.Thr421Lys	missense splice_region	Exon 8 of 13	NP_001116698.1	Q9Y2Z2-6
	MTO1	NM_133645.3		c.1335+193C>A		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>A	p.Thr421Lys	missense splice_region	Exon 8 of 13	ENSP00000402038.2	Q9Y2Z2-6
	MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1260+193C>A		intron	N/A	ENSP00000419561.2	Q9Y2Z2-4
	MTO1	ENST00000370300.8	TSL:1	c.1335+193C>A		intron	N/A	ENSP00000359323.4	Q9Y2Z2-1

Frequencies

GnomAD3 genomes AF: 0.0000468 AC: 5 AN: 106782 Hom.: 0 Cov.: 23

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: 1 AN: 373098 Hom.: 0 Cov.: 6 AF XY: 0.00000505 AC XY: 1 AN XY: 197910

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

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: 0.0000239 AC: 1 AN: 41776

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

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000468 AC: 5 AN: 106832 Hom.: 0 Cov.: 23 AF XY: 0.0000207 AC XY: 1 AN XY: 48290

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

African (AFR) AF: 0.00 AC: 0 AN: 27196

American (AMR) AF: 0.000136 AC: 1 AN: 7344

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

East Asian (EAS) AF: 0.000305 AC: 1 AN: 3282

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

European-Finnish (FIN) AF: 0.000356 AC: 1 AN: 2812

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

European-Non Finnish (NFE) AF: 0.0000347 AC: 2 AN: 57574

Other (OTH) AF: 0.00 AC: 0 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.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	4.8
DANN	Benign	0.72
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.0
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.014
Sift	Benign	0.14	T
Sift4G	Uncertain	0.034	D
gMVP		0.65
Mutation Taster		=96/4	polymorphism

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

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;