rs773023974
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_018006.5(TRMU):c.1135G>T(p.Gly379Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,132 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
Consequence
NM_018006.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251018Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135796
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461132Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726872
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
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Published functional studies support this variant is associated with impaired mitochondrial protein synthesis (PMID: 38113276); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25326635, 28973083, 37184518, 38113276) -
Inborn genetic diseases Pathogenic:1
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TRMU-related disorder Pathogenic:1
The TRMU c.1135G>T variant is predicted to result in the amino acid substitution p.Gly379Cys. This variant was reported in the homozygous state or with a second TRMU variant in individuals with infantile liver failure (Meng et al 2017. PubMed ID: 28973083; Squires et al. 2023. PubMed ID: 37184518). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -
not specified Uncertain:1
Variant summary: TRMU c.1135G>T (p.Gly379Cys) results in a non-conservative amino acid change located in the tRNA-specific 2-thiouridylase MnmA-like, C-terminal domain (IPR046885) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251018 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1135G>T has been reported in the literature with a second variant (c.497C>A; p.Ala166Glu) in at least one individual affected with Liver Failure Acute Infantile, Transient (e.g. Meng_2017). This report does not provide unequivocal conclusions about association of the variant with Liver Failure Acute Infantile, Transient. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28973083). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: two submitters classify the variant as likely pathogenic, and two submitters classify the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Uncertain:1
This variant was found once in our laboratory with another variant (A166E; phase undetermined) in a 2-month-old female with liver failure & metabolic acidosis. Heterozygotes would be expected to be asymptomatic carriers. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at