rs11090865

Variant names:

• chr22-46335792-G-T
• rs11090865
• NM_018006.5:c.28G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-46335792-G-T
• chr22-46335792-G-A

Variant summary

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

The NM_018006.5(TRMU):​c.28G>T​(p.Ala10Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,560,954 control chromosomes in the GnomAD database, including 9,396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1535 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7861 hom.)
• Consequence: TRMU NM_018006.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 8.01
• Publications: 58 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 (MetaRNN=0.0020942986).
• BP6: Variant 22-46335792-G-T is Benign according to our data. Variant chr22-46335792-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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.28G>T	p.Ala10Ser	missense	Exon 1 of 11	NP_060476.2
	TRMU	NM_001282785.2		c.28G>T	p.Ala10Ser	missense	Exon 1 of 10	NP_001269714.1	O75648-2
	TRMU	NM_001282782.2		c.-208G>T		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.28G>T	p.Ala10Ser	missense	Exon 1 of 11	ENSP00000496496.1	O75648-1
	TRMU	ENST00000381019.3	TSL:1	c.28G>T	p.Ala10Ser	missense	Exon 1 of 10	ENSP00000370407.3	O75648-2
	TRMU	ENST00000441818.5	TSL:1	n.28G>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000393014.1	Q2PPL5

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19602 AN: 152084 Hom.: 1533 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.0965

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0977

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.0900 AC: 14561 AN: 161732 AF XY: 0.0886

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.0579

Gnomad ASJ exome AF: 0.0932

Gnomad EAS exome AF: 0.000316

Gnomad FIN exome AF: 0.0980

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.0960

GnomAD4 exome AF: 0.101 AC: 142212 AN: 1408752 Hom.: 7861 Cov.: 31 AF XY: 0.0993 AC XY: 69293 AN XY: 697494

African (AFR) AF: 0.228 AC: 7338 AN: 32226

American (AMR) AF: 0.0617 AC: 2362 AN: 38294

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 2275 AN: 25402

East Asian (EAS) AF: 0.000244 AC: 9 AN: 36852

South Asian (SAS) AF: 0.0583 AC: 4732 AN: 81160

European-Finnish (FIN) AF: 0.0931 AC: 3763 AN: 40424

Middle Eastern (MID) AF: 0.0821 AC: 467 AN: 5688

European-Non Finnish (NFE) AF: 0.106 AC: 115394 AN: 1090140

Other (OTH) AF: 0.100 AC: 5872 AN: 58566

GnomAD4 genome AF: 0.129 AC: 19623 AN: 152202 Hom.: 1535 Cov.: 33 AF XY: 0.125 AC XY: 9276 AN XY: 74442

African (AFR) AF: 0.216 AC: 8957 AN: 41526

American (AMR) AF: 0.0853 AC: 1306 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0965 AC: 335 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0443 AC: 214 AN: 4834

European-Finnish (FIN) AF: 0.0977 AC: 1036 AN: 10608

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.109 AC: 7400 AN: 67972

Other (OTH) AF: 0.111 AC: 235 AN: 2110

Alfa AF: 0.108 Hom.: 3208

Bravo AF: 0.132

TwinsUK AF: 0.100 AC: 371

ALSPAC AF: 0.106 AC: 409

ESP6500AA AF: 0.203 AC: 847

ESP6500EA AF: 0.0988 AC: 805

ExAC AF: 0.0749 AC: 8489

Asia WGS AF: 0.0320 AC: 111 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (4)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Aminoglycoside-induced deafness;C3278664:Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (1)
-	-	-	Deafness, mitochondrial, modifier of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.21
MPC		0.44
ClinPred		0.061	T
GERP RS		4.5
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.72
Mutation Taster		=94/6	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: rs11090865; hg19: chr22-46731689; COSMIC: COSV51990139; COSMIC: COSV51990139;