22-46356036-AGCTGTGCAG-AGCTGTGCAGGCTGTGCAG

Variant names:

• chr22-46356036-A-AGCTGTGCAG
• rs753112330
• NM_018006.5:c.1073_1081dupAGGCTGTGC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_018006.5(TRMU):​c.1073_1081dupAGGCTGTGC​(p.Gln358_Val360dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: TRMU NM_018006.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 2.19
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018006.5.
• PP5: Variant 22-46356036-A-AGCTGTGCAG is Pathogenic according to our data. Variant chr22-46356036-A-AGCTGTGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552491.

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.1073_1081dupAGGCTGTGC	p.Gln358_Val360dup	disruptive_inframe_insertion	Exon 10 of 11	NP_060476.2
	TRMU	NM_001282782.2		c.731_739dupAGGCTGTGC	p.Gln244_Val246dup	disruptive_inframe_insertion	Exon 9 of 10	NP_001269711.1
	TRMU	NM_001282783.2		c.653_661dupAGGCTGTGC	p.Gln218_Val220dup	disruptive_inframe_insertion	Exon 9 of 10	NP_001269712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMU	ENST00000645190.1	MANE Select	c.1073_1081dupAGGCTGTGC	p.Gln358_Val360dup	disruptive_inframe_insertion	Exon 10 of 11	ENSP00000496496.1	O75648-1
	TRMU	ENST00000381019.3	TSL:1	c.1018+456_1018+464dupAGGCTGTGC		intron	N/A	ENSP00000370407.3	O75648-2
	TRMU	ENST00000441818.5	TSL:1	n.*607_*615dupAGGCTGTGC		non_coding_transcript_exon	Exon 9 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251186 AF XY: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727164

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000674 AC: 75 AN: 1111978

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

African (AFR) AF: 0.000121 AC: 5 AN: 41434

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: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	2	-	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (6)
2	1	-	not provided (3)
1	-	-	Aminoglycoside-induced deafness (1)
1	-	-	Aminoglycoside-induced deafness;C3278664:Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=83/17	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753112330; hg19: chr22-46751933;