rs141601555

Variant names:

• chr22-46335637-A-G
• rs141601555
• ENST00000441818.5:n.-128A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-46335637-A-G
• chr22-46335637-A-C
• chr22-46335637-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000867893.1(TRMU):​c.-128A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 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 ENST00000867893.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.269
• Publications: 0 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 -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 VariationId is 341998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0753 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.-128A>G		upstream_gene	N/A	NP_060476.2
	TRMU	NM_001282785.2		c.-128A>G		upstream_gene	N/A	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-363A>G		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.-128A>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-128A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5
	TRMU	ENST00000441818.5	TSL:1	n.-128A>G		5_prime_UTR	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

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

African (AFR) AF: 0.00295 AC: 59 AN: 20000

American (AMR) AF: 0.0779 AC: 2507 AN: 32194

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 290 AN: 19760

East Asian (EAS) AF: 0.0418 AC: 1319 AN: 31532

South Asian (SAS) AF: 0.00684 AC: 441 AN: 64438

European-Finnish (FIN) AF: 0.0511 AC: 1665 AN: 32568

Middle Eastern (MID) AF: 0.00251 AC: 8 AN: 3192

European-Non Finnish (NFE) AF: 0.0136 AC: 9544 AN: 701674

Other (OTH) AF: 0.0172 AC: 740 AN: 43128

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

African (AFR) AF: 0.00352 AC: 146 AN: 41424

American (AMR) AF: 0.0408 AC: 623 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.0309 AC: 159 AN: 5152

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4818

European-Finnish (FIN) AF: 0.0485 AC: 513 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0136 AC: 923 AN: 67940

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.00857 Hom.: 3

Bravo AF: 0.0169

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.76
CADD	Benign	6.2
DANN	Benign	0.70
PhyloP100		-0.27
PromoterAI		-0.0066	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs141601555; hg19: chr22-46731534;