dbSNP rs184994382: TRMU:n.-87T>C (chr22-46335678-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000867893.1(TRMU):c.-87T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,454,302 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 44 hom. )

Consequence

TRMU
ENST00000867893.1 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.80

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 22-46335678-T-C is Benign according to our data. Variant chr22-46335678-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 342001.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00209 (316/151314) while in subpopulation EAS AF = 0.0197 (100/5074). AF 95% confidence interval is 0.0166. There are 7 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,Mitochondrial gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000867893.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TRMU	NM_018006.5	MANE Select	c.-87T>C	upstream_gene	N/A	NP_060476.2
TRMU	NM_001282785.2		c.-87T>C	upstream_gene	N/A	NP_001269714.1	O75648-2
TRMU	NM_001282782.2		c.-322T>C	upstream_gene	N/A	NP_001269711.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TRMU	ENST00000441818.5	TSL:1	n.-87T>C	non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
TRMU	ENST00000456595.5	TSL:1	n.-87T>C	non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5
TRMU	ENST00000441818.5	TSL:1	n.-87T>C	5_prime_UTR	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

314

AN:

151200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000731

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.0197

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.00190

AC:

2471

AN:

1302988

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1235

AN XY:

646358

show subpopulations

African (AFR)

AF:

0.000105

AC:

AN:

28632

American (AMR)

AF:

0.000114

AC:

AN:

35116

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

24322

East Asian (EAS)

AF:

0.0410

AC:

1420

AN:

34624

South Asian (SAS)

AF:

0.000182

AC:

AN:

77046

European-Finnish (FIN)

AF:

0.0133

AC:

477

AN:

35786

Middle Eastern (MID)

AF:

0.000737

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.000426

AC:

430

AN:

1008478

Other (OTH)

AF:

0.00168

AC:

AN:

54914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

127

254

380

507

634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00209

AC:

316

AN:

151314

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

214

AN XY:

74022

show subpopulations

African (AFR)

AF:

0.0000729

AC:

AN:

41150

American (AMR)

AF:

0.000394

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3462

East Asian (EAS)

AF:

0.0197

AC:

100

AN:

5074

South Asian (SAS)

AF:

0.000624

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0122

AC:

128

AN:

10492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00102

AC:

AN:

67786

Other (OTH)

AF:

0.00143

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.000612

Asia WGS

AF:

0.0190

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.17

(source)

DANN

Benign

0.52

PhyloP100

-2.8

PromoterAI

-0.048

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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