22-46353829-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_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 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

Publications

9 publications found

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 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

TRMU links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMU	NM_018006.5 link	c.835G>A	p.Val279Met	missense_variant	Exon 8 of 11	ENST00000645190.1	NP_060476.2	O75648-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMU	ENST00000645190.1 link	c.835G>A	p.Val279Met	missense_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.000167

AC:

AN:

251408

AF XY:

0.000206

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 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

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.000475

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000229

AC:

255

AN:

1111878

Other (OTH)

AF:

0.000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41582

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000179

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

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 22, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_VSTR,PS3_MOD,PM2_SUP,PP3 -

Mar 31, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TRMU protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Dec 28, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Inborn genetic diseases

Pathogenic:1

Sep 22, 2015

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aminoglycoside-induced deafness

Pathogenic:1

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.

PhyloP100

9.1

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

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over