rs139608228

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTO1	NM_012123.4	c.1549G>A	p.Val517Met	missense_variant	9/12	ENST00000498286.6
MTO1	NM_001123226.2	c.1669G>A	p.Val557Met	missense_variant	10/13
MTO1	NM_133645.3	c.1624G>A	p.Val542Met	missense_variant	10/13
MTO1	XM_047418605.1	c.*27G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTO1	ENST00000498286.6	c.1549G>A	p.Val517Met	missense_variant	9/12	1	NM_012123.4	P1

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

GnomAD3 exomes AF: 0.00173 AC: 435 AN: 251244 Hom.: 2 AF XY: 0.00185 AC XY: 251 AN XY: 135830

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00212

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

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00226 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

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MTO1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	This variant is associated with the following publications: (PMID: 29458409) -

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;T;T;T;D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0069	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.48	N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.028	B;B;.;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

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

LitVar

Other links and lift over

dbSNP: rs139608228; hg19: chr6-74192255;