rs139608228

Variant names:

• chr6-73482532-G-A
• rs139608228
• NM_012123.4:c.1549G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-73482532-G-A
• chr6-73482532-G-T

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.1549G>A​(p.Val517Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,612,684 control chromosomes in the GnomAD database, including 7 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: MTO1 NM_012123.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.51
• Publications: 6 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=0.006876081).
• BP6: Variant 6-73482532-G-A is Benign according to our data. Variant chr6-73482532-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (224/152266) while in subpopulation NFE AF = 0.00185 (126/68022). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	NM_012123.4	MANE Select	c.1549G>A	p.Val517Met	missense	Exon 9 of 12	NP_036255.2	Q9Y2Z2-4
	MTO1	NM_001123226.2		c.1669G>A	p.Val557Met	missense	Exon 10 of 13	NP_001116698.1	Q9Y2Z2-6
	MTO1	NM_133645.3		c.1624G>A	p.Val542Met	missense	Exon 10 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.1549G>A	p.Val517Met	missense	Exon 9 of 12	ENSP00000419561.2	Q9Y2Z2-4
	MTO1	ENST00000415954.6	TSL:1	c.1669G>A	p.Val557Met	missense	Exon 10 of 13	ENSP00000402038.2	Q9Y2Z2-6
	MTO1	ENST00000370300.8	TSL:1	c.1624G>A	p.Val542Met	missense	Exon 10 of 13	ENSP00000359323.4	Q9Y2Z2-1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00173 AC: 435 AN: 251244 AF XY: 0.00185

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00174 AC: 2538 AN: 1460418 Hom.: 7 Cov.: 31 AF XY: 0.00175 AC XY: 1275 AN XY: 726584

African (AFR) AF: 0.000449 AC: 15 AN: 33436

American (AMR) AF: 0.000850 AC: 38 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 372 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86200

European-Finnish (FIN) AF: 0.000505 AC: 27 AN: 53414

Middle Eastern (MID) AF: 0.000613 AC: 3 AN: 4896

European-Non Finnish (NFE) AF: 0.00175 AC: 1944 AN: 1111674

Other (OTH) AF: 0.00212 AC: 128 AN: 60262

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74440

African (AFR) AF: 0.000698 AC: 29 AN: 41574

American (AMR) AF: 0.00138 AC: 21 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00185 AC: 126 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00159

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.093
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.066
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.028	B
Vest4		0.30
MVP		0.38
MPC		0.30
ClinPred		0.0080	T
GERP RS		4.5
Varity_R		0.047
gMVP		0.44
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs139608228; hg19: chr6-74192255;