chr22-46335637-A-G

Position:

• chr22-46335637-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000441818.5(TRMU):​c.-128A>G 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 0.0173 in 1,100,446 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 32)
  • Exomes 𝑓: 0.017 (297 hom.)
• Consequence: TRMU ENST00000441818.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.269

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 22-46335637-A-G is Benign according to our data. Variant chr22-46335637-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 341998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-46335637-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

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.-128A>G		5_prime_UTR_variant, NMD_transcript_variant	1/10	1
TRMU	ENST00000456595.5	c.-128A>G		5_prime_UTR_variant, NMD_transcript_variant	1/9	1
TRMU	ENST00000381021.7	c.-128A>G		5_prime_UTR_variant, NMD_transcript_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2464 AN: 151848 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0175 AC: 16573 AN: 948486 Hom.: 297 Cov.: 13 AF XY: 0.0168 AC XY: 8116 AN XY: 481852

Gnomad4 AFR exome AF: 0.00295

Gnomad4 AMR exome AF: 0.0779

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0418

Gnomad4 SAS exome AF: 0.00684

Gnomad4 FIN exome AF: 0.0511

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0162 AC: 2465 AN: 151960 Hom.: 38 Cov.: 32 AF XY: 0.0183 AC XY: 1358 AN XY: 74308

Gnomad4 AFR AF: 0.00352

Gnomad4 AMR AF: 0.0408

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.0309

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0485

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00857 Hom.: 3

Bravo AF: 0.0169

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.2
DANN	Benign	0.70

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: rs141601555; hg19: chr22-46731534;