rs138469662

chr6-73479825-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012123.4(MTO1):c.919G>A(p.Glu307Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTO1 NM_012123.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTO1	NM_012123.4	c.919G>A	p.Glu307Lys	missense_variant	5/12	ENST00000498286.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTO1	ENST00000498286.6	c.919G>A	p.Glu307Lys	missense_variant	5/12	1	NM_012123.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460510 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726660

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Nov 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.066	D
MutationAssessor	Uncertain	2.3	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.29
MutPred		0.49		Gain of MoRF binding (P = 0.0048);Gain of MoRF binding (P = 0.0048);.;Gain of MoRF binding (P = 0.0048);
MVP		0.88
MPC		0.94
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs138469662; hg19: chr6-74189548; COSMIC: COSV64774639; COSMIC: COSV64774639;