rs387907022

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_018006.5(TRMU):c.835G>A(p.Val279Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

TRMU
NM_018006.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.05

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-46353829-G-A is Pathogenic according to our data. Variant chr22-46353829-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-46353829-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMU	NM_018006.5 linkuse as main transcript	c.835G>A	p.Val279Met	missense_variant	8/11	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.835G>A	p.Val279Met	missense_variant	8/11		NM_018006.5	ENSP00000496496.1		O75648-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251408

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000214

AC:

313

AN:

1461682

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

161

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000131

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000220

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 22, 2024	Criteria applied: PM3_VSTR,PS3_MOD,PM2_SUP,PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 07, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 26, 2022	Variant summary: TRMU c.835G>A (p.Val279Met) results in a conservative amino acid change in 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 0.00017 in 251408 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TRMU causing Transient, Acute Infantile Liver Failure (0.00017 vs 0.0011), allowing no conclusion about variant significance. c.835G>A has been reported in the literature in multiple compound heterozygous individuals affected with Transient, Acute Infantile Liver Failure (example: Zeharia_2009, Uusimaa_2011, Gaignard_2013, Grover_2015, Nicastro_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Alotaibi M et al. (2020) Discoveries Reports. 3 :e7 https://www.discoveriesjournals.org/discoveries-reports/DRep.2020.OACS-Alotaibi.pdf; This variant is associated with the following publications: (PMID: 21931168, 28562522, 19732863, 31980526, 34426522, 31589614, Alotaibi_2020_Article, 33083013, 33084218, 31160058, 23625533, 25665837, 38113276, 36939041, 33629572, 37272928) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 279 of the TRMU protein (p.Val279Met). This variant is present in population databases (rs387907022, gnomAD 0.06%). This missense change has been observed in individual(s) with acute infantile liver failure or infantile reversible respiratory chain deficiency (PMID: 19732863, 21931168, 23625533, 25665837). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30819). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2015

- -

Aminoglycoside-induced deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;D;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

H;H;H;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

D;.;D;.;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.015

D;.;D;.;.

Sift4G

Uncertain

0.029

D;.;D;.;.

Polyphen

0.99

D;D;D;.;.

Vest4

0.99

MVP

0.75

MPC

0.33

ClinPred

0.88

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.90

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