rs1060499776

Positions:

• chr6-73497766-T-A
• chr6-73497766-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_012123.4(MTO1):​c.1787T>A​(p.Leu596Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MTO1 NM_012123.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.70

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 (HGNC:):

EEF1A1 (HGNC:3189): (eukaryotic translation elongation factor 1 alpha 1) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas, and the other isoform (alpha 2) is expressed in brain, heart and skeletal muscle. This isoform is identified as an autoantigen in 66% of patients with Felty syndrome. This gene has been found to have multiple copies on many chromosomes, some of which, if not all, represent different pseudogenes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-73497766-T-A is Pathogenic according to our data. Variant chr6-73497766-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402214.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-73497766-T-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.20089751). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTO1	NM_012123.4	c.1787T>A	p.Leu596Gln	missense_variant	11/12	ENST00000498286.6	NP_036255.2
MTO1	NM_001123226.2	c.1907T>A	p.Leu636Gln	missense_variant	12/13		NP_001116698.1
MTO1	NM_133645.3	c.1862T>A	p.Leu621Gln	missense_variant	12/13		NP_598400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6	c.1787T>A	p.Leu596Gln	missense_variant	11/12	1	NM_012123.4	ENSP00000419561.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.22
DEOGEN2	Benign	0.078	.;.;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	.;.;.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.0	N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.57
MutPred		0.38		.;.;.;Gain of disorder (P = 0.0172);
MVP		0.36
MPC		0.26
ClinPred		0.68	D
GERP RS		4.6
Varity_R		0.049
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1060499776; hg19: chr6-74207489;