chr22-46335486-G-A

Position:

• chr22-46335486-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.-279G>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 0.0142 in 502,326 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 33)
  • Exomes 𝑓: 0.015 (61 hom.)
• Consequence: TRMU ENST00000441818.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.446

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=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1973/152338) while in subpopulation NFE AF= 0.0187 (1273/68020). AF 95% confidence interval is 0.0179. There are 25 homozygotes in gnomad4. There are 975 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 25 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.-279G>A		5_prime_UTR_variant, NMD_transcript_variant	1/10	1
TRMU	ENST00000456595.5	c.-279G>A		5_prime_UTR_variant, NMD_transcript_variant	1/9	1
TRMU	ENST00000381021.7	c.-279G>A		5_prime_UTR_variant, NMD_transcript_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152220 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0147 AC: 5151 AN: 349988 Hom.: 61 Cov.: 0 AF XY: 0.0146 AC XY: 2703 AN XY: 184876

Gnomad4 AFR exome AF: 0.00303

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00762

Gnomad4 FIN exome AF: 0.00873

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0130 AC: 1973 AN: 152338 Hom.: 25 Cov.: 33 AF XY: 0.0131 AC XY: 975 AN XY: 74496

Gnomad4 AFR AF: 0.00365

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00827

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0137 Hom.: 4

Bravo AF: 0.0126

Asia WGS AF: 0.00318 AC: 11 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	-0.78
CADD	Benign	6.3
DANN	Benign	0.81

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: rs187162795; hg19: chr22-46731383;