rs751248771

Positions:

chr22-46335804-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018006.5(TRMU):c.40G>A(p.Gly14Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,561,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TRMU
NM_018006.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.01

Variant links:

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 links:

TRMU (HGNC:):

TRMU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMU	NM_018006.5 linkuse as main transcript	c.40G>A	p.Gly14Ser	missense_variant	1/11	ENST00000645190.1	NP_060476.2	O75648-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMU	ENST00000645190.1 linkuse as main transcript	c.40G>A	p.Gly14Ser	missense_variant	1/11		NM_018006.5	ENSP00000496496.1		O75648-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000431

AC:

AN:

162286

Hom.:

AF XY:

0.0000335

AC XY:

AN XY:

89512

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000733

Gnomad ASJ exome

AF:

0.000466

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1409422

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

697876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000521

Gnomad4 ASJ exome

AF:

0.000472

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000768

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000872

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 07, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2020

Identified as heterozygous in an individual with infantile liver failure, hepatomegaly, current age 5 of years; A second variant was not described (Boczonadi et al., 2015); Analysis in patient cells harboring G14S showed reduced mitochondrial enzymatic activities of Complex I and IV and the 2-thiouridylation levels of the mitochondrial tRNAs were markedly reduced (Zeharia et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19732863, 25407320, 21910628) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 07, 2022

- -

TRMU-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The TRMU c.40G>A variant is predicted to result in the amino acid substitution p.Gly14Ser. This variant was reported in an individual with acute infantile liver failure (Zeharia et al 2009. PubMed ID: 19732863). Biochemical experiments revealed this patient had reduced mitochondrial enzymatic activity, and was heterozygous for the c.40G>A variant on the paternal allele with a seemingly non-expressing maternal allele (Zeharia et al 2009. PubMed ID: 19732863). This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;.;H

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

D;.;.;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Pathogenic

0.0

D;.;.;D

Polyphen

1.0

D;D;.;D

Vest4

0.93

MutPred

0.97

Loss of stability (P = 0.0953);Loss of stability (P = 0.0953);Loss of stability (P = 0.0953);Loss of stability (P = 0.0953);

MVP

0.83

MPC

0.38

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.98

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over