NM_012123.4:c.1638-118_1638-116delAAA

Variant names:

• chr6-73492103-CAAA-C
• rs5877369
• NM_012123.4:c.1638-118_1638-116delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012123.4(MTO1):​c.1638-118_1638-116delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 472,626 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 0)
  • Exomes 𝑓: 0.048 (0 hom.)
• Consequence: MTO1 NM_012123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.464
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0693) population. However there is too low homozygotes in high coverage region: (expected more than 133, got 0).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	NM_012123.4	MANE Select	c.1638-118_1638-116delAAA		intron	N/A	NP_036255.2	Q9Y2Z2-4
	MTO1	NM_001123226.2		c.1758-118_1758-116delAAA		intron	N/A	NP_001116698.1	Q9Y2Z2-6
	MTO1	NM_133645.3		c.1713-118_1713-116delAAA		intron	N/A	NP_598400.1	Q9Y2Z2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTO1	ENST00000498286.6	TSL:1 MANE Select	c.1638-118_1638-116delAAA		intron	N/A	ENSP00000419561.2	Q9Y2Z2-4
	MTO1	ENST00000415954.6	TSL:1	c.1758-118_1758-116delAAA		intron	N/A	ENSP00000402038.2	Q9Y2Z2-6
	MTO1	ENST00000370300.8	TSL:1	c.1713-118_1713-116delAAA		intron	N/A	ENSP00000359323.4	Q9Y2Z2-1

Frequencies

GnomAD3 genomes AF: 0.000432 AC: 61 AN: 141182 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000285

Gnomad ASJ AF: 0.000297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00267

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000446

Gnomad OTH AF: 0.000519

GnomAD4 exome AF: 0.0478 AC: 15838 AN: 331384 Hom.: 0 AF XY: 0.0487 AC XY: 8695 AN XY: 178548

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0225 AC: 191 AN: 8492

American (AMR) AF: 0.0255 AC: 378 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 467 AN: 8896

East Asian (EAS) AF: 0.0490 AC: 995 AN: 20316

South Asian (SAS) AF: 0.0715 AC: 2764 AN: 38652

European-Finnish (FIN) AF: 0.0432 AC: 799 AN: 18514

Middle Eastern (MID) AF: 0.0567 AC: 78 AN: 1376

European-Non Finnish (NFE) AF: 0.0460 AC: 9345 AN: 202972

Other (OTH) AF: 0.0474 AC: 821 AN: 17332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000432 AC: 61 AN: 141242 Hom.: 0 Cov.: 0 AF XY: 0.000470 AC XY: 32 AN XY: 68142

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000795 AC: 3 AN: 37740

American (AMR) AF: 0.000285 AC: 4 AN: 14058

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 1 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4880

South Asian (SAS) AF: 0.00 AC: 0 AN: 4480

European-Finnish (FIN) AF: 0.00267 AC: 23 AN: 8624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000446 AC: 29 AN: 64988

Other (OTH) AF: 0.000513 AC: 1 AN: 1948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 706

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5877369; hg19: chr6-74201826;