rs118203990
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_018006.5(TRMU):āc.229T>Cā(p.Tyr77His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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 Pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y77Y) has been classified as Likely benign.
Frequency
Consequence
NM_018006.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRMU | NM_018006.5 | c.229T>C | p.Tyr77His | missense_variant | 2/11 | ENST00000645190.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRMU | ENST00000645190.1 | c.229T>C | p.Tyr77His | missense_variant | 2/11 | NM_018006.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251496Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2009 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 77 of the TRMU protein (p.Tyr77His). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRMU protein function. ClinVar contains an entry for this variant (Variation ID: 1291). This missense change has been observed in individuals with acute infantile liver failure (PMID: 19732863). This variant is present in population databases (rs118203990, gnomAD 0.01%). - |
Aminoglycoside-induced deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
TRMU-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | The TRMU c.229T>C variant is predicted to result in the amino acid substitution p.Tyr77His. This variant was reported as homozygous or compound heterozygous state in multiple individuals with infantile liver failure (Zeharia et al 2009. PubMed ID: 19732863; Vogel et al 2023. PubMed ID: 36305855). This variant is one of the most common disease causing variants in TRMU in association with reversible acute liver failure of infancy. This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at