chr22-46335587-G-A

Variant names:

• chr22-46335587-G-A
• rs114587018
• ENST00000441818.5:n.-178G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000867893.1(TRMU):​c.-178G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00806 in 694,158 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (193 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (40 hom.)
• Consequence: TRMU ENST00000867893.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.82
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 22-46335587-G-A is Benign according to our data. Variant chr22-46335587-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMU	NM_018006.5	MANE Select	c.-178G>A		upstream_gene	N/A	NP_060476.2
	TRMU	NM_001282785.2		c.-178G>A		upstream_gene	N/A	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-413G>A		upstream_gene	N/A	NP_001269711.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMU	ENST00000441818.5	TSL:1	n.-178G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-178G>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5
	TRMU	ENST00000441818.5	TSL:1	n.-178G>A		5_prime_UTR	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4149 AN: 151944 Hom.: 194 Cov.: 33

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00265 AC: 1437 AN: 542096 Hom.: 40 Cov.: 7 AF XY: 0.00232 AC XY: 657 AN XY: 283702

African (AFR) AF: 0.0818 AC: 903 AN: 11044

American (AMR) AF: 0.00620 AC: 127 AN: 20474

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 70 AN: 13978

East Asian (EAS) AF: 0.00 AC: 0 AN: 27132

South Asian (SAS) AF: 0.000332 AC: 16 AN: 48170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29522

Middle Eastern (MID) AF: 0.00369 AC: 8 AN: 2166

European-Non Finnish (NFE) AF: 0.000319 AC: 115 AN: 360822

Other (OTH) AF: 0.00688 AC: 198 AN: 28788

GnomAD4 genome AF: 0.0273 AC: 4157 AN: 152062 Hom.: 193 Cov.: 33 AF XY: 0.0263 AC XY: 1956 AN XY: 74352

African (AFR) AF: 0.0941 AC: 3904 AN: 41472

American (AMR) AF: 0.0107 AC: 164 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67938

Other (OTH) AF: 0.0166 AC: 35 AN: 2108

Alfa AF: 0.0191 Hom.: 14

Bravo AF: 0.0311

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.82
DANN	Benign	0.84
PhyloP100		-1.8
PromoterAI		-0.036	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs114587018; hg19: chr22-46731484;