22-46335792-G-T

Position:

chr22-46335792-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018006.5(TRMU):c.28G>T(p.Ala10Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,560,954 control chromosomes in the GnomAD database, including 9,396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1535 hom., cov: 33)

Exomes 𝑓: 0.10 ( 7861 hom. )

Consequence

TRMU
NM_018006.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020942986).

BP6

Variant 22-46335792-G-T is Benign according to our data. Variant chr22-46335792-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-46335792-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMU	NM_018006.5 linkuse as main transcript	c.28G>T	p.Ala10Ser	missense_variant	1/11	ENST00000645190.1	NP_060476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMU	ENST00000645190.1 linkuse as main transcript	c.28G>T	p.Ala10Ser	missense_variant	1/11		NM_018006.5	ENSP00000496496	P1	O75648-1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19602

AN:

152084

Hom.:

1533

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0855

Gnomad ASJ

AF:

0.0965

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0451

Gnomad FIN

AF:

0.0977

Gnomad MID

AF:

0.124

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.113

GnomAD3 exomes

AF:

0.0900

AC:

14561

AN:

161732

Hom.:

885

AF XY:

0.0886

AC XY:

7895

AN XY:

89110

show subpopulations

Gnomad AFR exome

AF:

0.239

Gnomad AMR exome

AF:

0.0579

Gnomad ASJ exome

AF:

0.0932

Gnomad EAS exome

AF:

0.000316

Gnomad SAS exome

AF:

0.0580

Gnomad FIN exome

AF:

0.0980

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.0960

GnomAD4 exome

AF:

0.101

AC:

142212

AN:

1408752

Hom.:

7861

Cov.:

AF XY:

0.0993

AC XY:

69293

AN XY:

697494

show subpopulations

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.0617

Gnomad4 ASJ exome

AF:

0.0896

Gnomad4 EAS exome

AF:

0.000244

Gnomad4 SAS exome

AF:

0.0583

Gnomad4 FIN exome

AF:

0.0931

Gnomad4 NFE exome

AF:

0.106

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

AF:

0.129

AC:

19623

AN:

152202

Hom.:

1535

Cov.:

AF XY:

0.125

AC XY:

9276

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.216

Gnomad4 AMR

AF:

0.0853

Gnomad4 ASJ

AF:

0.0965

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0443

Gnomad4 FIN

AF:

0.0977

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0999

Hom.:

1285

Bravo

AF:

0.132

TwinsUK

AF:

0.100

AC:

371

ALSPAC

AF:

0.106

AC:

409

ESP6500AA

AF:

0.203

AC:

847

ESP6500EA

AF:

0.0988

AC:

805

ExAC

AF:

0.0749

AC:

8489

Asia WGS

AF:

0.0320

AC:

111

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 11, 2017	- -

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 02, 2021

- -

Deafness, mitochondrial, modifier of

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

.;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.4

M;M;.;M

MutationTaster

Benign

3.6e-7

P;P

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.0

N;.;.;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.016

D;.;.;D

Sift4G

Uncertain

0.012

D;.;.;D

Polyphen

1.0

D;D;.;D

Vest4

0.21

MPC

0.44

ClinPred

0.061

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.72

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