chr22-46335604-A-C

Variant names:

• chr22-46335604-A-C
• rs886057607
• ENST00000441818.5:n.-161A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000867893.1(TRMU):​c.-161A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 805,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TRMU ENST00000867893.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.564
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.-161A>C		upstream_gene	N/A	NP_060476.2
	TRMU	NM_001282785.2		c.-161A>C		upstream_gene	N/A	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-396A>C		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.-161A>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-161A>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5
	TRMU	ENST00000441818.5	TSL:1	n.-161A>C		5_prime_UTR	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151808 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000480

GnomAD4 exome AF: 0.000168 AC: 110 AN: 653498 Hom.: 0 Cov.: 9 AF XY: 0.000204 AC XY: 69 AN XY: 338854

African (AFR) AF: 0.00 AC: 0 AN: 13376

American (AMR) AF: 0.00 AC: 0 AN: 24482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15460

East Asian (EAS) AF: 0.00 AC: 0 AN: 28336

South Asian (SAS) AF: 0.00 AC: 0 AN: 52502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2490

European-Non Finnish (NFE) AF: 0.000238 AC: 108 AN: 454038

Other (OTH) AF: 0.0000612 AC: 2 AN: 32698

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151808 Hom.: 0 Cov.: 33 AF XY: 0.0000809 AC XY: 6 AN XY: 74144

African (AFR) AF: 0.0000242 AC: 1 AN: 41334

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67910

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.27
PhyloP100		-0.56
PromoterAI		-0.049	Neutral
Mutation Taster		=300/0	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: rs886057607; hg19: chr22-46731501;