NM_018006.5:c.2T>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Supporting PM2 PP5

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 Conflicting classifications of pathogenicity (no stars).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 36 codons. Genomic position: 46337802. Lost 0.084 part of the original CDS.
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215292.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMU	NM_018006.5	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENST00000645190.1	NP_060476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMU	ENST00000645190.1	c.2T>G	p.Met1?	start_lost	Exon 1 of 11		NM_018006.5	ENSP00000496496.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000687 AC: 1 AN: 145610 Hom.: 0 AF XY: 0.0000125 AC XY: 1 AN XY: 79758

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000738

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 11, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Mar 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 215292). Disruption of the initiator codon has been observed in individuals with acute infantile liver failure (PMID: 19732863, 33365252). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects the initiator methionine of the TRMU mRNA. The next in-frame methionine is located at codon 36. -

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Pathogenic:1

Apr 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TRMU c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is located at codon 36 and to our knowledge, no pathogenic or likely pathogenic variants upstream of this alternate translation codon have been reported. However, at-least two other pathogenic/likely pathogenic variants impacting the same initiation codon, c.2T>A and c.2T>C have been reported in infants affected with Acute Infantile Liver Failure (PMID 33365252 and 31395954). Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-06 in 145610 control chromosomes. To our knowledge, no occurrence of c.2T>G in individuals affected with Liver Failure Acute Infantile, Transient and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 215292). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aminoglycoside-induced deafness;C3278664:Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Pathogenic:1

Jun 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.36	T
PROVEAN	Benign	-2.0	N;.;.;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0020	D;.;.;D
Polyphen		0.97	D;D;.;P
Vest4		0.87
MutPred		0.98		Gain of MoRF binding (P = 0.006);Gain of MoRF binding (P = 0.006);Gain of MoRF binding (P = 0.006);Gain of MoRF binding (P = 0.006);
MVP		0.90
ClinPred		0.98	D
GERP RS		1.8
Varity_R		0.95
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203992; hg19: chr22-46731663;