6-73497873-C-T

Variant names:

• chr6-73497873-C-T
• rs117757245
• NM_012123.4:c.1894C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001123226.2(MTO1):​c.2014C>T​(p.Leu672Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,612,248 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0085 (89 hom.)
• Consequence: MTO1 NM_001123226.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.549
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 6-73497873-C-T is Benign according to our data. Variant chr6-73497873-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.549 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00495 (753/152222) while in subpopulation NFE AF = 0.0092 (626/68024). AF 95% confidence interval is 0.00861. There are 3 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001123226.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	NM_012123.4	MANE Select	c.1894C>T	p.Leu632Leu	synonymous	Exon 11 of 12	NP_036255.2
	MTO1	NM_001123226.2		c.2014C>T	p.Leu672Leu	synonymous	Exon 12 of 13	NP_001116698.1
	MTO1	NM_133645.3		c.1969C>T	p.Leu657Leu	synonymous	Exon 12 of 13	NP_598400.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1894C>T	p.Leu632Leu	synonymous	Exon 11 of 12	ENSP00000419561.2
	MTO1	ENST00000415954.6	TSL:1	c.2014C>T	p.Leu672Leu	synonymous	Exon 12 of 13	ENSP00000402038.2
	MTO1	ENST00000370300.8	TSL:1	c.1969C>T	p.Leu657Leu	synonymous	Exon 12 of 13	ENSP00000359323.4

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152104 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00497 AC: 1248 AN: 251042 AF XY: 0.00467

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00894

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00852 AC: 12433 AN: 1460026 Hom.: 89 Cov.: 30 AF XY: 0.00811 AC XY: 5886 AN XY: 726150

African (AFR) AF: 0.00146 AC: 49 AN: 33462

American (AMR) AF: 0.00284 AC: 127 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00193 AC: 166 AN: 86126

European-Finnish (FIN) AF: 0.00173 AC: 92 AN: 53290

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0104 AC: 11546 AN: 1110640

Other (OTH) AF: 0.00723 AC: 436 AN: 60328

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152222 Hom.: 3 Cov.: 30 AF XY: 0.00431 AC XY: 321 AN XY: 74410

African (AFR) AF: 0.00159 AC: 66 AN: 41536

American (AMR) AF: 0.00216 AC: 33 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00920 AC: 626 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00680 Hom.: 6

Bravo AF: 0.00503

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00855

EpiControl AF: 0.00771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs117757245; hg19: chr6-74207596;