chr22-46335484-G-A

Position:

• chr22-46335484-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000441818.5(TRMU):​c.-281G>A 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 0.00545 in 498,356 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (10 hom.)
• Consequence: TRMU ENST00000441818.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -4.86

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00642 (978/152332) while in subpopulation AFR AF= 0.00787 (327/41574). AF 95% confidence interval is 0.00716. There are 4 homozygotes in gnomad4. There are 466 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMU	ENST00000441818.5	c.-281G>A		5_prime_UTR_variant, NMD_transcript_variant	1/10	1
TRMU	ENST00000456595.5	c.-281G>A		5_prime_UTR_variant, NMD_transcript_variant	1/9	1
TRMU	ENST00000381021.7	c.-281G>A		5_prime_UTR_variant, NMD_transcript_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 979 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00503 AC: 1739 AN: 346024 Hom.: 10 Cov.: 0 AF XY: 0.00485 AC XY: 887 AN XY: 182850

Gnomad4 AFR exome AF: 0.00737

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00164

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00274

Gnomad4 NFE exome AF: 0.00668

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00642 AC: 978 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00626 AC XY: 466 AN XY: 74492

Gnomad4 AFR AF: 0.00787

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00736

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00614 Hom.: 0

Bravo AF: 0.00674

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.16
DANN	Benign	0.85

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: rs148373924; hg19: chr22-46731381;