chr22-46335678-T-G

Variant names:

• chr22-46335678-T-G
• rs184994382
• ENST00000441818.5:n.-87T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000867893.1(TRMU):​c.-87T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,302,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: TRMU ENST00000867893.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80
• Publications: 0 publications found

Genes affected

TRMU (HGNC:25481): (tRNA mitochondrial 2-thiouridylase) This nuclear gene encodes a mitochondrial tRNA-modifying enzyme. The encoded protein catalyzes the 2-thiolation of uridine on the wobble positions of tRNA(Lys), tRNA(Glu), and tRNA(Gln), resulting in the formation of 5-taurinomethyl-2-thiouridine moieties. Mutations in this gene may cause transient infantile liver failure. Polymorphisms in this gene may also influence the severity of deafness caused by mitochondrial 12S ribosomal RNA mutations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

TRMU Gene-Disease associations (from GenCC):

• acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial myopathy with reversible cytochrome C oxidase deficiency

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000867893.1. 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
	TRMU	NM_018006.5	MANE Select	c.-87T>G		upstream_gene	N/A	NP_060476.2
	TRMU	NM_001282785.2		c.-87T>G		upstream_gene	N/A	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-322T>G		upstream_gene	N/A	NP_001269711.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMU	ENST00000441818.5	TSL:1	n.-87T>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-87T>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5
	TRMU	ENST00000441818.5	TSL:1	n.-87T>G		5_prime_UTR	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1302992 Hom.: 0 Cov.: 22 AF XY: 0.00000155 AC XY: 1 AN XY: 646360

African (AFR) AF: 0.00 AC: 0 AN: 28632

American (AMR) AF: 0.00 AC: 0 AN: 35116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24322

East Asian (EAS) AF: 0.00 AC: 0 AN: 34626

South Asian (SAS) AF: 0.00 AC: 0 AN: 77046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 9.92e-7 AC: 1 AN: 1008478

Other (OTH) AF: 0.00 AC: 0 AN: 54914

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.099
DANN	Benign	0.55
PhyloP100		-2.8
PromoterAI		-0.077	Neutral

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: rs184994382; hg19: chr22-46731575;