rs118203992

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-46335766-T-A
• chr22-46335766-T-C
• chr22-46335766-T-G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_018006.5(TRMU):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRMU NM_018006.5 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 13 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-A is Pathogenic according to our data. Variant chr22-46335766-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1294.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.088	T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	-0.27	T
PhyloP100		2.0
PROVEAN	Benign	-2.0	N;.;.;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0020	D;.;.;D
Polyphen		0.97	D;D;.;P
Vest4		0.89
MutPred		0.99		Gain of MoRF binding (P = 0.0153);Gain of MoRF binding (P = 0.0153);Gain of MoRF binding (P = 0.0153);Gain of MoRF binding (P = 0.0153);
MVP		0.90
ClinPred		0.98	D
GERP RS		1.8
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.65
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;