chr22-46335729-C-G

Variant names:

• chr22-46335729-C-G
• rs560661382
• NM_018006.5:c.-36C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_018006.5(TRMU):​c.-36C>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 0.0000838 in 1,540,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: TRMU NM_018006.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.23
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 22-46335729-C-G is Benign according to our data. Variant chr22-46335729-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 384230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018006.5. 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.-36C>G		5_prime_UTR	Exon 1 of 11	NP_060476.2
	TRMU	NM_001282785.2		c.-36C>G		5_prime_UTR	Exon 1 of 10	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-271C>G		5_prime_UTR	Exon 1 of 10	NP_001269711.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMU	ENST00000645190.1	MANE Select	c.-36C>G		5_prime_UTR	Exon 1 of 11	ENSP00000496496.1	O75648-1
	TRMU	ENST00000441818.5	TSL:1	n.-36C>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5
	TRMU	ENST00000456595.5	TSL:1	n.-36C>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000413880.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000125 AC: 17 AN: 135940 AF XY: 0.0000944

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000497 AC: 69 AN: 1387832 Hom.: 0 Cov.: 30 AF XY: 0.0000394 AC XY: 27 AN XY: 685110

African (AFR) AF: 0.00179 AC: 56 AN: 31316

American (AMR) AF: 0.0000558 AC: 2 AN: 35862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39758

Middle Eastern (MID) AF: 0.000196 AC: 1 AN: 5100

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1078020

Other (OTH) AF: 0.000156 AC: 9 AN: 57784

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74462

African (AFR) AF: 0.00142 AC: 59 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000468

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		1.2
PromoterAI		-0.026	Neutral

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: rs560661382; hg19: chr22-46731626;