6-73461661-C-A

Variant names:

• chr6-73461661-C-A
• rs12198468
• ENST00000415954.6:c.-194C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000415954.6(MTO1):​c.-194C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 472,276 control chromosomes in the GnomAD database, including 198,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.90 (62035 hom., cov: 34)
  • Exomes 𝑓: 0.92 (136491 hom.)
• Consequence: MTO1 ENST00000415954.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54
• Publications: 4 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]

MTO1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-73461661-C-A is Benign according to our data. Variant chr6-73461661-C-A is described in ClinVar as [Benign]. Clinvar id is 1272952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTO1	NM_012123.4	c.-194C>A		upstream_gene_variant		ENST00000498286.6	NP_036255.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTO1	ENST00000498286.6	c.-194C>A		upstream_gene_variant		1	NM_012123.4	ENSP00000419561.2

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137120 AN: 152006 Hom.: 61993 Cov.: 34

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.842

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.886

GnomAD4 exome AF: 0.923 AC: 295416 AN: 320152 Hom.: 136491 Cov.: 0 AF XY: 0.922 AC XY: 152650 AN XY: 165492

African (AFR) AF: 0.863 AC: 8184 AN: 9488

American (AMR) AF: 0.893 AC: 9814 AN: 10996

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 8808 AN: 10414

East Asian (EAS) AF: 0.925 AC: 23523 AN: 25422

South Asian (SAS) AF: 0.927 AC: 15975 AN: 17226

European-Finnish (FIN) AF: 0.954 AC: 28095 AN: 29452

Middle Eastern (MID) AF: 0.849 AC: 1244 AN: 1466

European-Non Finnish (NFE) AF: 0.928 AC: 181945 AN: 196128

Other (OTH) AF: 0.911 AC: 17828 AN: 19560

GnomAD4 genome AF: 0.902 AC: 137220 AN: 152124 Hom.: 62035 Cov.: 34 AF XY: 0.903 AC XY: 67178 AN XY: 74388

African (AFR) AF: 0.855 AC: 35458 AN: 41494

American (AMR) AF: 0.873 AC: 13341 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.842 AC: 2918 AN: 3466

East Asian (EAS) AF: 0.954 AC: 4947 AN: 5186

South Asian (SAS) AF: 0.931 AC: 4492 AN: 4826

European-Finnish (FIN) AF: 0.956 AC: 10088 AN: 10552

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.927 AC: 63016 AN: 67998

Other (OTH) AF: 0.886 AC: 1872 AN: 2112

Alfa AF: 0.911 Hom.: 7861

Bravo AF: 0.896

Asia WGS AF: 0.940 AC: 3210 AN: 3414

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-1.5
PromoterAI		-0.028	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12198468; hg19: chr6-74171384;