22-46335766-T-G

Variant names:

• chr22-46335766-T-G
• rs118203992
• NM_018006.5:c.2T>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_018006.5(TRMU):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,398,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: TRMU NM_018006.5 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.03
• Publications: 6 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 36 codons. Genomic position: 46337802. Lost 0.084 part of the original CDS.
• PS1: Another start lost variant in NM_018006.5 (TRMU) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-46335766-T-G is Pathogenic according to our data. Variant chr22-46335766-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 215292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2T>G	p.Met1?	start_lost	Exon 1 of 11	NP_060476.2
	TRMU	NM_001282785.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 10	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-234T>G		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.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000496496.1	O75648-1
	TRMU	ENST00000381019.3	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000370407.3	O75648-2
	TRMU	ENST00000441818.5	TSL:1	n.2T>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000687 AC: 1 AN: 145610 AF XY: 0.0000125

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1398764 Hom.: 0 Cov.: 30 AF XY: 0.00000578 AC XY: 4 AN XY: 691494

African (AFR) AF: 0.00 AC: 0 AN: 31750

American (AMR) AF: 0.00 AC: 0 AN: 36916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.00 AC: 0 AN: 36104

South Asian (SAS) AF: 0.00 AC: 0 AN: 80112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00000738 AC: 8 AN: 1084062

Other (OTH) AF: 0.00 AC: 0 AN: 58224

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (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
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.36	T
PhyloP100		2.0
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.87
MutPred		0.98		Gain of MoRF binding (P = 0.006)
MVP		0.90
ClinPred		0.98	D
GERP RS		1.8
PromoterAI		0.027	Neutral
Varity_R		0.95
gMVP		0.67
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs118203992; hg19: chr22-46731663;