22-46335678-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000441818.5(TRMU):c.-87T>C variant causes a 5 prime UTR, NMD transcript 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 ENST00000441818.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.80

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 342001.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMU	NM_018006.5			upstream_gene_variant		ENST00000645190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMU	ENST00000645190.1			upstream_gene_variant			NM_018006.5	P1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 314 AN: 151200 Hom.: 7 Cov.: 33

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.: 44 Cov.: 22 AF XY: 0.00191 AC XY: 1235 AN XY: 646358

Gnomad4 AFR exome AF: 0.000105

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0410

Gnomad4 SAS exome AF: 0.000182

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.000426

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.00209 AC: 316 AN: 151314 Hom.: 7 Cov.: 33 AF XY: 0.00289 AC XY: 214 AN XY: 74022

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.00102

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.000612

Asia WGS AF: 0.0190 AC: 67 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.17
Dann	Benign	0.52

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

Other links and lift over

dbSNP: rs184994382; hg19: chr22-46731575;