Genetic Variant TRMU:n.287-2485T>C (chr22-46335294-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The ENST00000486620.5(TRMU):n.287-2485T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 212,974 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.033 ( 295 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

TRMU
ENST00000486620.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.686

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 22-46335294-T-C is Benign according to our data. Variant chr22-46335294-T-C is described in ClinVar as Benign. ClinVar VariationId is 1227604.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000486620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TRMU	ENST00000486620.5	TSL:3	n.287-2485T>C	intron	N/A
TRMU	ENST00000441818.5	TSL:1	n.-471T>C	upstream_gene	N/A	ENSP00000393014.1	Q2PPL5
TRMU	ENST00000456595.5	TSL:1	n.-471T>C	upstream_gene	N/A	ENSP00000413880.1	Q2PPL5

Frequencies

GnomAD3 genomes

AF:

0.0334

AC:

5086

AN:

152188

Hom.:

296

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.0253

GnomAD4 exome

AF:

0.00135

AC:

AN:

60668

Hom.:

AF XY:

0.00122

AC XY:

AN XY:

32098

show subpopulations

African (AFR)

AF:

0.0828

AC:

AN:

338

American (AMR)

AF:

0.0114

AC:

AN:

1318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1332

East Asian (EAS)

AF:

0.00

AC:

AN:

806

South Asian (SAS)

AF:

0.000419

AC:

AN:

11924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4316

Middle Eastern (MID)

AF:

0.00431

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.000380

AC:

AN:

36850

Other (OTH)

AF:

0.00535

AC:

AN:

3552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0334

AC:

5086

AN:

152306

Hom.:

295

Cov.:

AF XY:

0.0325

AC XY:

2418

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.114

AC:

4730

AN:

41540

American (AMR)

AF:

0.0159

AC:

244

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68028

Other (OTH)

AF:

0.0250

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

224

448

671

895

1119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0311

Hom.:

Bravo

AF:

0.0378

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

2.7

(source)

DANN

Benign

0.88

PhyloP100

-0.69

PromoterAI

0.031

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over