dbSNP rs115654622: MTO1:p.Thr456Thr (chr6-73482147-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012123.4(MTO1):c.1368T>C(p.Thr456Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000948 in 1,614,186 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 5 hom. )

Consequence

MTO1
NM_012123.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -5.32

Publications

5 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: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

MTO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 6-73482147-T-C is Benign according to our data. Variant chr6-73482147-T-C is described in ClinVar as Benign. ClinVar VariationId is 138275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.32 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00423 (644/152294) while in subpopulation AFR AF = 0.0136 (566/41556). AF 95% confidence interval is 0.0127. There are 4 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 Unknown,AR 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTO1	NM_012123.4	MANE Select	c.1368T>C	p.Thr456Thr	synonymous	Exon 8 of 12	NP_036255.2	Q9Y2Z2-4
MTO1	NM_001123226.2		c.1488T>C	p.Thr496Thr	synonymous	Exon 9 of 13	NP_001116698.1	Q9Y2Z2-6
MTO1	NM_133645.3		c.1443T>C	p.Thr481Thr	synonymous	Exon 9 of 13	NP_598400.1	Q9Y2Z2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1368T>C	p.Thr456Thr	synonymous	Exon 8 of 12	ENSP00000419561.2	Q9Y2Z2-4
MTO1	ENST00000415954.6	TSL:1	c.1488T>C	p.Thr496Thr	synonymous	Exon 9 of 13	ENSP00000402038.2	Q9Y2Z2-6
MTO1	ENST00000370300.8	TSL:1	c.1443T>C	p.Thr481Thr	synonymous	Exon 9 of 13	ENSP00000359323.4	Q9Y2Z2-1

Frequencies

GnomAD3 genomes

AF:

0.00422

AC:

642

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00140

AC:

351

AN:

251488

AF XY:

0.00112

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000606

AC:

886

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000573

AC XY:

417

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0131

AC:

439

AN:

33480

American (AMR)

AF:

0.00125

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000154

AC:

171

AN:

1112010

Other (OTH)

AF:

0.00197

AC:

119

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00423

AC:

644

AN:

152294

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0136

AC:

566

AN:

41556

American (AMR)

AF:

0.00183

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68024

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.00469

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.13

(source)

DANN

Benign

0.52

PhyloP100

-5.3

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over