22-46335740-G-C

Variant names:

• chr22-46335740-G-C
• rs995131564
• NM_018006.5:c.-25G>C

Variant summary

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

The NM_018006.5(TRMU):​c.-25G>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 0.00000518 in 1,544,388 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: TRMU NM_018006.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.190
• 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=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018006.5. 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.-25G>C		5_prime_UTR	Exon 1 of 11	NP_060476.2
	TRMU	NM_001282785.2		c.-25G>C		5_prime_UTR	Exon 1 of 10	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-260G>C		5_prime_UTR	Exon 1 of 10	NP_001269711.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMU	ENST00000645190.1	MANE Select	c.-25G>C		5_prime_UTR	Exon 1 of 11	ENSP00000496496.1	O75648-1
	TRMU	ENST00000441818.5	TSL:1	n.-25G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-25G>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000715 AC: 1 AN: 139852 AF XY: 0.0000131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1392156 Hom.: 0 Cov.: 30 AF XY: 0.00000582 AC XY: 4 AN XY: 687502

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.00 AC: 0 AN: 36198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35812

South Asian (SAS) AF: 0.00 AC: 0 AN: 79510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 0.00000648 AC: 7 AN: 1080254

Other (OTH) AF: 0.00 AC: 0 AN: 57898

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.9
DANN	Benign	0.67
PhyloP100		0.19
PromoterAI		-0.66	Under-expression

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: rs995131564; hg19: chr22-46731637;