rs73452515

Variant names:

• chr6-73500567-T-G
• rs73452515
• NM_012123.4:c.1918-7T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_012123.4(MTO1):​c.1918-7T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,608,822 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (387 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (351 hom.)
• Consequence: MTO1 NM_012123.4 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.08
• Publications: 2 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]

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

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-73500567-T-G is Benign according to our data. Variant chr6-73500567-T-G is described in ClinVar as Benign. ClinVar VariationId is 138278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	NM_012123.4	MANE Select	c.1918-7T>G		splice_region intron	N/A	NP_036255.2
	MTO1	NM_001123226.2		c.2038-7T>G		splice_region intron	N/A	NP_001116698.1
	MTO1	NM_133645.3		c.1993-7T>G		splice_region intron	N/A	NP_598400.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1918-7T>G		splice_region intron	N/A	ENSP00000419561.2
	MTO1	ENST00000415954.6	TSL:1	c.2038-7T>G		splice_region intron	N/A	ENSP00000402038.2
	MTO1	ENST00000370300.8	TSL:1	c.1993-7T>G		splice_region intron	N/A	ENSP00000359323.4

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5985 AN: 152154 Hom.: 386 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0109 AC: 2672 AN: 244714 AF XY: 0.00800

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00518

GnomAD4 exome AF: 0.00417 AC: 6072 AN: 1456550 Hom.: 351 Cov.: 30 AF XY: 0.00357 AC XY: 2583 AN XY: 724476

African (AFR) AF: 0.140 AC: 4650 AN: 33164

American (AMR) AF: 0.00859 AC: 371 AN: 43196

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.000470 AC: 40 AN: 85158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00976 AC: 56 AN: 5740

European-Non Finnish (NFE) AF: 0.000365 AC: 405 AN: 1110186

Other (OTH) AF: 0.00912 AC: 549 AN: 60204

GnomAD4 genome AF: 0.0394 AC: 5994 AN: 152272 Hom.: 387 Cov.: 33 AF XY: 0.0375 AC XY: 2794 AN XY: 74456

African (AFR) AF: 0.136 AC: 5656 AN: 41538

American (AMR) AF: 0.0161 AC: 246 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68026

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0202 Hom.: 109

Bravo AF: 0.0449

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.000548

EpiControl AF: 0.000772

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (1)
-	-	1	MTO1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	21
DANN	Benign	0.66
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.63		Position offset: 1
DS_AL_spliceai		0.45		Position offset: 7

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

Other links and lift over

dbSNP: rs73452515; hg19: chr6-74210290;