rs144075994

Variant names:

• chr6-73480048-A-G
• rs144075994
• NM_012123.4:c.1051A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012123.4(MTO1):​c.1051A>G​(p.Met351Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,614,186 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M351T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: MTO1 NM_012123.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.53
• Publications: 1 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: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015490919).
• BP6: Variant 6-73480048-A-G is Benign according to our data. Variant chr6-73480048-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00238 (362/152324) while in subpopulation AFR AF = 0.00844 (351/41576). AF 95% confidence interval is 0.00771. There are 5 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012123.4. 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.1051A>G	p.Met351Val	missense	Exon 6 of 12	NP_036255.2	Q9Y2Z2-4
	MTO1	NM_001123226.2		c.1051A>G	p.Met351Val	missense	Exon 6 of 13	NP_001116698.1	Q9Y2Z2-6
	MTO1	NM_133645.3		c.1051A>G	p.Met351Val	missense	Exon 6 of 13	NP_598400.1	Q9Y2Z2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1051A>G	p.Met351Val	missense	Exon 6 of 12	ENSP00000419561.2	Q9Y2Z2-4
	MTO1	ENST00000415954.6	TSL:1	c.1051A>G	p.Met351Val	missense	Exon 6 of 13	ENSP00000402038.2	Q9Y2Z2-6
	MTO1	ENST00000370300.8	TSL:1	c.1051A>G	p.Met351Val	missense	Exon 6 of 13	ENSP00000359323.4	Q9Y2Z2-1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152206 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000624 AC: 157 AN: 251424 AF XY: 0.000434

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000275 AC: 402 AN: 1461862 Hom.: 3 Cov.: 31 AF XY: 0.000246 AC XY: 179 AN XY: 727232

African (AFR) AF: 0.00971 AC: 325 AN: 33476

American (AMR) AF: 0.000224 AC: 10 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111994

Other (OTH) AF: 0.000563 AC: 34 AN: 60396

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152324 Hom.: 5 Cov.: 31 AF XY: 0.00223 AC XY: 166 AN XY: 74478

African (AFR) AF: 0.00844 AC: 351 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00105 Hom.: 2

Bravo AF: 0.00272

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000832 AC: 101

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.60
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.63
MPC		0.25
ClinPred		0.0080	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.58
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs144075994; hg19: chr6-74189771; COSMIC: COSV106109373; COSMIC: COSV106109373;