6-73497764-A-G

Position:

• chr6-73497764-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_012123.4(MTO1):​c.1785A>G​(p.Gln595=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0081 in 1,613,972 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 30)
  • Exomes 𝑓: 0.0084 (69 hom.)
• Consequence: MTO1 NM_012123.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00400

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]

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 Benign. Variant got -14 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-73497764-A-G is Benign according to our data. Variant chr6-73497764-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138276.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 = 0.0056 (853/152322) while in subpopulation NFE AF= 0.00965 (656/68014). AF 95% confidence interval is 0.00903. There are 6 homozygotes in gnomad4. There are 375 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTO1	NM_012123.4	c.1785A>G	p.Gln595=	synonymous_variant	11/12	ENST00000498286.6	NP_036255.2
MTO1	NM_001123226.2	c.1905A>G	p.Gln635=	synonymous_variant	12/13		NP_001116698.1
MTO1	NM_133645.3	c.1860A>G	p.Gln620=	synonymous_variant	12/13		NP_598400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6	c.1785A>G	p.Gln595=	synonymous_variant	11/12	1	NM_012123.4	ENSP00000419561	P1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 853 AN: 152204 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00964

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00495 AC: 1245 AN: 251264 Hom.: 8 AF XY: 0.00501 AC XY: 680 AN XY: 135826

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00901

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00836 AC: 12225 AN: 1461650 Hom.: 69 Cov.: 30 AF XY: 0.00807 AC XY: 5867 AN XY: 727130

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00380

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00788

GnomAD4 genome AF: 0.00560 AC: 853 AN: 152322 Hom.: 6 Cov.: 30 AF XY: 0.00503 AC XY: 375 AN XY: 74506

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00965

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00771 Hom.: 3

Bravo AF: 0.00549

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

EEF1A1: BS2; MTO1: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: 1
DS_AL_spliceai		0.31		Position offset: -28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147990749; hg19: chr6-74207487;