rs116519615

Variant names:

• chr22-46335648-G-C
• rs116519615
• ENST00000441818.5:n.-117G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-46335648-G-C
• chr22-46335648-G-A

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.-117G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,223,912 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (200 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (90 hom.)
• Consequence: TRMU ENST00000867893.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.580
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-46335648-G-C is Benign according to our data. Variant chr22-46335648-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0926 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.-117G>C		upstream_gene	N/A	NP_060476.2
	TRMU	NM_001282785.2		c.-117G>C		upstream_gene	N/A	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-352G>C		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.-117G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-117G>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5
	TRMU	ENST00000441818.5	TSL:1	n.-117G>C		5_prime_UTR	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4192 AN: 152016 Hom.: 201 Cov.: 33

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

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: 0.000574

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00260 AC: 2784 AN: 1071782 Hom.: 90 Cov.: 14 AF XY: 0.00227 AC XY: 1226 AN XY: 539380

African (AFR) AF: 0.0846 AC: 1926 AN: 22754

American (AMR) AF: 0.00596 AC: 200 AN: 33558

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 98 AN: 21336

East Asian (EAS) AF: 0.00 AC: 0 AN: 32680

South Asian (SAS) AF: 0.000290 AC: 20 AN: 69024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33366

Middle Eastern (MID) AF: 0.00460 AC: 16 AN: 3482

European-Non Finnish (NFE) AF: 0.000270 AC: 218 AN: 808292

Other (OTH) AF: 0.00647 AC: 306 AN: 47290

GnomAD4 genome AF: 0.0276 AC: 4200 AN: 152130 Hom.: 200 Cov.: 33 AF XY: 0.0266 AC XY: 1979 AN XY: 74410

African (AFR) AF: 0.0951 AC: 3945 AN: 41496

American (AMR) AF: 0.0108 AC: 165 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67976

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.000818 Hom.: 0

Bravo AF: 0.0314

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	-0.80
CADD	Benign	0.91
DANN	Benign	0.37
PhyloP100		-0.58
PromoterAI		0.20	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs116519615; hg19: chr22-46731545;