22-46335714-A-C

Variant names:

• chr22-46335714-A-C
• rs773460571
• NM_018006.5:c.-51A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_018006.5(TRMU):​c.-51A>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 0.000116 in 1,532,402 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TRMU NM_018006.5 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0590
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-46335714-A-C is Benign according to our data. Variant chr22-46335714-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3031221.Status of the report is no_assertion_criteria_provided, 0 stars.

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.-51A>C		5_prime_UTR	Exon 1 of 11	NP_060476.2
	TRMU	NM_001282785.2		c.-51A>C		5_prime_UTR	Exon 1 of 10	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-286A>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.-51A>C		5_prime_UTR	Exon 1 of 11	ENSP00000496496.1	O75648-1
	TRMU	ENST00000441818.5	TSL:1	n.-51A>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-51A>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000225 AC: 3 AN: 133530 AF XY: 0.00

Gnomad AFR exome AF: 0.000316

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: 0.0000201

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 163 AN: 1380274 Hom.: 0 Cov.: 29 AF XY: 0.000114 AC XY: 78 AN XY: 681484

African (AFR) AF: 0.000483 AC: 15 AN: 31054

American (AMR) AF: 0.00 AC: 0 AN: 35632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 35564

South Asian (SAS) AF: 0.00 AC: 0 AN: 78960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4744

European-Non Finnish (NFE) AF: 0.000135 AC: 145 AN: 1073068

Other (OTH) AF: 0.0000522 AC: 3 AN: 57500

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

African (AFR) AF: 0.000241 AC: 10 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000140

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TRMU-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.90
PhyloP100		0.059
PromoterAI		0.17	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: rs773460571; hg19: chr22-46731611;