RTRAF

Summary

RTRAF (RNA transcription, translation and transport factor, HGNC:23169) is a protein-coding gene on chromosome 14q22.1, encoding tRNA-splicing ligase complex subunit RTRAF (Q9Y224). Accessory subunit of the tRNA-splicing ligase complex that acts by directly joining spliced tRNA halves to mature-sized tRNAs by incorporating the precursor-derived splice junction phosphate into the mature tRNA as a canonical 3’,5’-phosphodiester. It is a selective cancer dependency (DepMap: 39.7% of cell lines).

Enables RNA binding activity and RNA polymerase II complex binding activity. Involved in negative regulation of protein kinase activity; positive regulation of transcription by RNA polymerase II; and tRNA splicing, via endonucleolytic cleavage and ligation. Located in microtubule cytoskeleton; nucleoplasm; and perinuclear region of cytoplasm. Part of tRNA-splicing ligase complex.

Source: NCBI Gene 51637 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 16 total
• GTEx eGene: eQTL in 13 tissues, sQTL in 19 (q < 0.05)
• Cancer dependency (DepMap): dependent in 39.7% of screened cell lines
• Constraint (gnomAD): pLI 0.71 (intermediate), LOEUF 0.65 (unconstrained)
• MANE Select transcript: NM_016039
• Interaction hub: 2,170 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23169
Approved symbol	RTRAF
Name	RNA transcription, translation and transport factor
Location	14q22.1
Locus type	gene with protein product
Status	Approved
Aliases	TSLIG4, CGI-99, RLLM1, CLE, CLE7, LCRP369, hCLE1
Ensembl gene	ENSG00000087302
Ensembl biotype	protein_coding
OMIM	610858
Entrez	51637

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 14 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron

MANE Select: ENST00000261700

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3, TSL 3: 1, TSL 4: 1, TSL 5: 1

ENST00000261700, ENST00000553362, ENST00000553479, ENST00000553707, ENST00000555319, ENST00000556760, ENST00000557553, ENST00000902518, ENST00000902519, ENST00000902520, ENST00000920645, ENST00000920646, ENST00000920647, ENST00000920648, ENST00000920649, ENST00000942315, ENST00001034529, ENST00001082767, ENST00001082768, ENST00001082778, ENST00001123765, ENST00001132968

RefSeq mRNA: 1 — MANE Select: NM_016039 NM_016039

CCDS: CCDS9705

Canonical transcript exons

ENST00000261700 — 8 exons

Exon	Start	End
ENSE00000657239	51991317	51991441
ENSE00000657245	52004194	52004242
ENSE00000854696	51989546	51989700
ENSE00001227381	51993723	51993822
ENSE00001365973	52004362	52010694
ENSE00003629113	51999708	51999796
ENSE00003661809	52001798	52001866
ENSE00003684928	51998494	51998580

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 247.9264 / max 1457.4527, expressed in 1827 samples.

Highest expression (Bgee): secondary oocyte, oocyte, primordial germ cell in gonad, testis, cartilage tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RTRAF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 19 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 32 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	5.0e-22	-2.10	14:51999784:G:A
Cells Cultured fibroblasts	eqtl	3.7e-12	-0.17	14:52014034:A:G
Testis	sqtl	7.7e-11	-1.94	14:51999784:G:A
Cells EBV-transformed lymphocytes	sqtl	3.9e-10	-2.53	14:51999784:G:A
Adipose Subcutaneous	sqtl	5.6e-08	-0.54	14:51996979:T:C
Thyroid	eqtl	8.1e-08	-0.21	14:52090932:G:A
Esophagus Mucosa	sqtl	3.8e-06	-1.42	14:51999784:G:A
Skin Sun Exposed Lower leg	sqtl	4.6e-06	+1.17	14:51999784:G:A
Muscle Skeletal	sqtl	1.0e-05	-1.14	14:51999784:G:A
Colon Transverse	sqtl	2.0e-05	-1.44	14:51999784:G:A
Adipose Visceral Omentum	sqtl	2.0e-04	-1.31	14:51999784:G:A
Breast Mammary Tissue	sqtl	2.9e-04	-0.52	14:52004171:A:G
Nerve Tibial	eqtl	3.4e-04	-0.10	14:52036369:A:G
Esophagus Muscularis	sqtl	4.6e-04	+1.26	14:51999784:G:A
Adipose Subcutaneous	eqtl	7.9e-04	-0.15	14:52003510:G:C
Minor Salivary Gland	eqtl	9.5e-04	+0.83	14:52163578:G:C
Skin Sun Exposed Lower leg	eqtl	1.6e-03	-0.34	14:52017105:A:G
Artery Aorta	sqtl	2.2e-03	-1.29	14:51999784:G:A
Adipose Visceral Omentum	eqtl	4.4e-03	-0.15	14:52010341:A:G
Esophagus Gastroesophageal Junction	eqtl	6.7e-03	-0.26	14:51879117:C:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
139598	243.2837	1827
139599	4.1383	1504
139601	0.4930	228
139600	0.0113	7

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.82	gold quality
oocyte	CL:0000023	99.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.48	gold quality
right testis	UBERON:0004534	99.46	gold quality
left testis	UBERON:0004533	99.44	gold quality
cartilage tissue	UBERON:0002418	99.03	gold quality
ganglionic eminence	UBERON:0004023	99.02	gold quality
calcaneal tendon	UBERON:0003701	98.99	gold quality
embryo	UBERON:0000922	98.98	gold quality
palpebral conjunctiva	UBERON:0001812	98.96	gold quality
adult organism	UBERON:0007023	98.93	gold quality
heart right ventricle	UBERON:0002080	98.89	gold quality
body of pancreas	UBERON:0001150	98.88	gold quality
tibia	UBERON:0000979	98.84	gold quality
heart left ventricle	UBERON:0002084	98.83	gold quality
cortical plate	UBERON:0005343	98.83	gold quality
cardiac ventricle	UBERON:0002082	98.82	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.82	gold quality
testis	UBERON:0000473	98.81	gold quality
lower esophagus	UBERON:0013473	98.81	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.74	gold quality
male germ cell	CL:0000015	98.73	gold quality
esophagus squamous epithelium	UBERON:0006920	98.71	gold quality
heart	UBERON:0000948	98.70	gold quality
body of stomach	UBERON:0001161	98.69	gold quality
right atrium auricular region	UBERON:0006631	98.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.67	gold quality
sperm	CL:0000019	98.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.66	gold quality
right adrenal gland cortex	UBERON:0035827	98.65	gold quality
right adrenal gland	UBERON:0001233	98.64	gold quality
skin of hip	UBERON:0001554	98.64	gold quality
upper leg skin	UBERON:0004262	98.64	gold quality
stromal cell of endometrium	CL:0002255	98.62	gold quality
islet of Langerhans	UBERON:0000006	98.62	gold quality
left adrenal gland	UBERON:0001234	98.62	gold quality
left adrenal gland cortex	UBERON:0035825	98.62	gold quality
mucosa of stomach	UBERON:0001199	98.61	gold quality
cardiac atrium	UBERON:0002081	98.61	gold quality
ventricular zone	UBERON:0003053	98.61	gold quality
left ovary	UBERON:0002119	98.60	gold quality
mucosa of transverse colon	UBERON:0004991	98.56	gold quality
adrenal cortex	UBERON:0001235	98.54	gold quality
right ovary	UBERON:0002118	98.54	gold quality
parietal pleura	UBERON:0002400	98.53	gold quality
nasal cavity mucosa	UBERON:0001826	98.52	gold quality
gastrocnemius	UBERON:0001388	98.50	gold quality
pancreas	UBERON:0001264	98.49	gold quality
germinal epithelium of ovary	UBERON:0001304	98.49	gold quality
adipose tissue	UBERON:0001013	98.48	gold quality
adrenal gland	UBERON:0002369	98.48	gold quality
left coronary artery	UBERON:0001626	98.47	gold quality
gingival epithelium	UBERON:0001949	98.47	gold quality
esophagus	UBERON:0001043	98.46	gold quality
right coronary artery	UBERON:0001625	98.46	gold quality
type B pancreatic cell	CL:0000169	98.45	gold quality
ovary	UBERON:0000992	98.45	gold quality
epithelium of esophagus	UBERON:0001976	98.45	gold quality
connective tissue	UBERON:0002384	98.45	gold quality
muscle of leg	UBERON:0001383	98.44	gold quality
pigmented layer of retina	UBERON:0001782	98.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.44	gold quality
pleura	UBERON:0000977	98.42	gold quality
descending thoracic aorta	UBERON:0002345	98.42	gold quality
thoracic mammary gland	UBERON:0005200	98.42	gold quality
mammary gland	UBERON:0001911	98.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.41	gold quality
coronary artery	UBERON:0001621	98.39	gold quality
tibial artery	UBERON:0007610	98.39	gold quality
left lobe of thyroid gland	UBERON:0001120	98.38	gold quality
popliteal artery	UBERON:0002250	98.38	gold quality
visceral pleura	UBERON:0002401	98.38	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.38	gold quality
gingiva	UBERON:0001828	98.36	gold quality
parotid gland	UBERON:0001831	98.36	gold quality
large intestine	UBERON:0000059	98.35	gold quality
right lobe of thyroid gland	UBERON:0001119	98.35	gold quality
colon	UBERON:0001155	98.35	gold quality
adenohypophysis	UBERON:0002196	98.35	gold quality
skin of abdomen	UBERON:0001416	98.34	gold quality
epithelium of nasopharynx	UBERON:0001951	98.34	gold quality
peritoneum	UBERON:0002358	98.34	gold quality
omental fat pad	UBERON:0010414	98.34	gold quality
oral cavity	UBERON:0000167	98.33	gold quality
stomach	UBERON:0000945	98.33	gold quality
aorta	UBERON:0000947	98.33	gold quality
fundus of stomach	UBERON:0001160	98.33	gold quality
zone of skin	UBERON:0000014	98.32	gold quality
mammalian vulva	UBERON:0000997	98.32	gold quality
vena cava	UBERON:0004087	98.30	gold quality
colonic mucosa	UBERON:0000317	98.29	gold quality
smooth muscle tissue	UBERON:0001135	98.29	gold quality
lymph node	UBERON:0000029	98.28	gold quality
endocervix	UBERON:0000458	98.28	gold quality
ascending aorta	UBERON:0001496	98.28	gold quality
thoracic aorta	UBERON:0001515	98.28	gold quality
thyroid gland	UBERON:0002046	98.28	gold quality
body of uterus	UBERON:0009853	98.28	gold quality
skin of leg	UBERON:0001511	98.27	gold quality
muscle organ	UBERON:0001630	98.27	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	4.47
E-MTAB-7606	no	511.52
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Testis	tissue	132.9	high
Bone marrow	tissue	131.0	medium
Heart muscle	tissue	129.8	medium
Skeletal muscle	tissue	115.6	medium
Pancreas	tissue	107.5	high
Spinal cord	tissue	104.2
Thymus	tissue	99.7
Tonsil	tissue	98.6	medium
Lymph node	tissue	98.5	medium
Tongue	tissue	95.3
Ovary	tissue	94.3	medium
Pons	tissue	92.6
Superior colliculi	tissue	87.7
Midbrain	tissue	86.4
Medulla oblongata	tissue	86.3
Thalamus	tissue	85.3
Rectum	tissue	83.2	high
Urinary bladder	tissue	82.2	high
Epididymis	tissue	82.1	high
Substantia nigra	tissue	80.7
Adrenal gland	tissue	79.7	high
Breast	tissue	77.8	high
Thyroid gland	tissue	76.0	high
Colon	tissue	74.9	high
Liver	tissue	73.7	medium
Adipose tissue	tissue	72.6	high
Salivary gland	tissue	72.3	medium
Kidney	tissue	72.0	medium
Smooth muscle	tissue	71.7	medium
Corpus callosum	tissue	69.8
Hippocampal formation	tissue	69.8
Appendix	tissue	69.6	high
Parathyroid gland	tissue	69.5	medium
Caudate putamen	tissue	69.0
Skin 1	tissue	68.8	high
Esophagus	tissue	68.7	medium
Frontal cortex	tissue	67.9
Putamen	tissue	66.9
Periaqueductal gray	tissue	65.9
Placenta	tissue	64.1	high
Endometrium 1	tissue	63.8	medium
Gallbladder	tissue	63.6	high
Septum	tissue	63.2
Pituitary gland	tissue	63.0
Cerebral cortex	tissue	62.1	high
Somatosensory cortex	tissue	62.1
Stomach 1	tissue	61.7	high
Prostate	tissue	61.1	medium
Hypothalamus	tissue	60.5
Cerebellum	tissue	60.3	high
Vagina	tissue	60.1	medium
Small intestine	tissue	59.5	high
Duodenum	tissue	57.7	medium
Cervix	tissue	56.5	high
Ventral forebrain	tissue	56.3
Occipital cortex	tissue	56.0
Seminal vesicle	tissue	55.3	medium
Fallopian tube	tissue	54.2	high
Spleen	tissue	53.2	high
Retina	tissue	52.2

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (104.2), Dorsal spinal cord (94.7), Blood vessel (94.1), Dorsal hippocampus (69.8), White matter (69.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting RTRAF by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

14 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-4501	98.72	67.19	921
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-216B-5P	97.16	66.76	1126
HSA-MIR-517-5P	97.13	68.43	781

Functional genomics

gnomAD constraint: pLI 0.709, LOEUF 0.645, missense Z -0.0346 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000261700 — one region, missense o/e 1.01. DepMap (CRISPR cell-line fitness): dependent in 39.7% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): HSC-4 (-1.257), TUHR4TKB (-1.134), JHH-7 (-1.122), Hs 766T (-1.059), HCC-827 (-0.987), TTC442 (-0.962), PA-1 [PA1] (-0.923), Mero-95 (-0.917), KCI-MOH1 (-0.916), MON (-0.914), UW228 (-0.913), SU-DHL-8 (-0.912), SF-295 (-0.906), BT-12 (-0.899), PANC-1 (-0.893).

Literature-anchored findings (GeneRIF, showing 13)

• A novel protein CGI-99 is isolated, which may be involved in the functional regulation of human ninein in the centrosome structure and may also be important in brain development and tumorigenesis. (PMID:15147888)
• c14orf166 was identified asa novel metastasis-associated protein, and the roles of radixin, moesin and c14orf166 in pancreatic cancer metastasis deserve further investigations. (PMID:19152423)
• spatial interactions of hnRNPH1, NF45, and C14orf166 with HCVc174 likely modulate HCV or cellular functions during acute and chronic HCV infection (PMID:21823664)
• Silencing of CLE causes reduction of influenza A virus polymerase activity, viral RNA transcription and replication, virus titer, and viral particle production. (PMID:21900157)
• hCLE/C14orf166 associates with DDX1, HSPC117, and FAM98B in a novel transcription-dependent shuttling RNA-transporting complex. (PMID:24608264)
• Overexpression of chromosome 14 open reading frame 166 correlates with disease progression in nasopharyngeal carcinoma. (PMID:25964093)
• C14ORF166 may represent a biomarker of pelvic lymph node metastasis in uterine cervical cancer (PMID:26219895)
• C14orf166, a cellular protein required for viral replication, is incorporated into influenza virus particles. (PMID:26864902)
• C14orf166 could be a novel prognostic biomarker of breast cancer, it also contributes to cell proliferation by regulating G1/S transition. (PMID:26883017)
• C14orf166 promotes bladder cancer cell proliferation and can be a novel prognostic biomarker for patients with bladder cancer. (PMID:26905879)
• the two structural homologs FAM98A and FAM98B included in a novel complex with DDX1 and C14orf166 are required for PRMT1 expression in colorectal cancer cell lines (PMID:28040436)
• Molecular architecture of the human tRNA ligase complex. (PMID:34854379)
• An in silico prediction of interaction models of influenza A virus PA and human C14orf166 protein from yeast-two-hybrid screening data. (PMID:37265372)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtraf	ENSDARG00000009253
mus_musculus	Rtraf	ENSMUSG00000021807
rattus_norvegicus	Rtraf	ENSRNOG00000000340
rattus_norvegicus	Rtraf-ps2	ENSRNOG00000029734
drosophila_melanogaster	CG31249	FBGN0051249
caenorhabditis_elegans		WBGENE00008457

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915295) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
tremors	1
decreased exploration in new environment	1
increased eosinophil cell number	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to tooth bud stage	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R8I2	100.0%	Diamond
Xenopus laevis	Q63ZS0	86.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GNG2	protein-coding	54331
NID2	protein-coding	22795
PTGDR	protein-coding	5729
LINC02319	ncRNA	105370498

Protein

Protein identifiers

tRNA-splicing ligase complex subunit RTRAF — Q9Y224 (reviewed: Q9Y224)

Alternative names: CLE7 homolog, RNA transcription, translation and transport factor protein

All UniProt accessions (5): G3V4C6, G3V4E7, Q9Y224, H0YJB9, Q549M8

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the tRNA-splicing ligase complex that acts by directly joining spliced tRNA halves to mature-sized tRNAs by incorporating the precursor-derived splice junction phosphate into the mature tRNA as a canonical 3’,5’-phosphodiester. RNA-binding protein involved in modulation of mRNA transcription by Polymerase II. Could also play a role in RNA transport. (Microbial infection) In case of infection by influenza virus A (IVA), is involved in viral replication.

Subunit / interactions. Homodimer. Component of the tRNA-splicing ligase core complex composed of the catalytic subunit RTCB and the accessory proteins DDX1, C2orf49/Ashwin/ASW, FAM98B and RTRAF/CGI-99. Interacts with FAM98A (via N- and C-terminus). Interacts with NIN; which may prevent phosphorylation of NIN. Interacts with POLR2A. (Microbial infection) Interacts with influenza A virus (IAV) RNA polymerase subunits PA, PB1 and PB2, and nucleocapsid NP. Associates with IAV polymerase complexes both in the nucleus and cytosol. Associates with IAV ribonucleoproteins (vRNP) packaged in virions. Interacts with hepatitis C virus core protein p19.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Perinuclear region. Cytoskeleton. Microtubule organizing center. Centrosome Nucleus.

Tissue specificity. Widely expressed. Expressed at high level in heart and skeletal muscle. Expressed at intermediate level in liver, pancreas, fetal brain and fetal lung. Weakly expressed in adult brain, adult lung, placenta, fetal liver and fetal kidney. Overexpressed in many brain tumors.

Induction. (Microbial infection) Up-regulated specifically following influenza A virus (IAV) infection in a viral replication-dependent manner (at protein level).

Similarity. Belongs to the RTRAF family.

RefSeq proteins (1): NP_057123* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019265	RTRAF	Family

Pfam: PF10036

UniProt features (12 total): helix 8, modified residue 3, chain 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
7P3A	N-terminal domain of CGI-99	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y224-F1	72.09	0.00

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3)

Type	Positions
N6-acetyllysine	20, 62, 98

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-6784531	tRNA processing in the nucleus	curated
R-HSA-8953854	Metabolism of RNA	—
R-HSA-72306	tRNA processing	—

MSigDB gene sets: 159 (showing top): YAATNRNNNYNATT_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, MODULE_151, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, CAGCTG_AP4_Q5, GOCC_MICROTUBULE_ORGANIZING_CENTER, MARTINEZ_RB1_TARGETS_DN

GO Biological Process (6): DNA-templated transcription (GO:0006351), tRNA splicing, via endonucleolytic cleavage and ligation (GO:0006388), negative regulation of protein kinase activity (GO:0006469), positive regulation of transcription by RNA polymerase II (GO:0045944), RNA transport (GO:0050658), tRNA processing (GO:0008033)

GO Molecular Function (4): RNA polymerase II complex binding (GO:0000993), RNA binding (GO:0003723), protein binding (GO:0005515), identical protein binding (GO:0042802)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471), tRNA-splicing ligase complex (GO:0072669), mitotic spindle (GO:0072686)

Reactome top-level categories

2 top-level categories:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

29 GO namespaces:

Category	Terms
cellular anatomical structure	4
cytoplasm	2
gene expression	1
RNA biosynthetic process	1
RNA splicing, via endonucleolytic cleavage and ligation	1
tRNA processing	1
negative regulation of protein phosphorylation	1
protein kinase activity	1
negative regulation of kinase activity	1
regulation of protein kinase activity	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
nucleic acid transport	1
establishment of RNA localization	1
RNA processing	1
tRNA metabolic process	1
RNA polymerase core enzyme binding	1
nucleic acid binding	1
binding	1
protein binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
intracellular protein-containing complex	1
catalytic complex	1
spindle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of protein kinase activity	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	mutant phenotype
tRNA splicing, via endonucleolytic cleavage and ligation	BP	mutant phenotype
centrosome	CC	direct assay
cytoplasm	CC	direct assay
mitotic spindle	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
tRNA-splicing ligase complex	CC	direct assay
RNA binding	MF	direct assay
RNA polymerase II complex binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,170 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTRAF	NIN	Q8N4C6	837
RTRAF	TSLIG3B	Q52LJ0	773
RTRAF	RTCB	Q9Y3I0	702
RTRAF	TSLIG2	Q9BVC5	663
RTRAF	DDX1	Q92499	655
RTRAF	TSLIG1	Q8IWT0	621
RTRAF	TSLIG3A	Q8NCA5	603
RTRAF	POLR2A	P24928	601
RTRAF	TXNDC16	Q9P2K2	467
RTRAF	SMU1	Q2TAY7	464
RTRAF	TMEM144	Q7Z5S9	464
RTRAF	GSK3B	P49841	462
RTRAF	FAABTP	Q96HH6	454
RTRAF	UBAP2L	Q14157	445
RTRAF	MED11	Q9P086	443

IntAct

Human interaction partners of RTRAF in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

15 partners by confidence:

Partner	Interaction type	MIscore	Records
FAM98A	physical association	0.810	6
RTCB	physical association	0.750	2
DDX1	physical association	0.720	1
PA	physical association	0.580	8
NIN	physical association	0.560	4
PSORS1C2	physical association	0.560	3
C2orf49	physical association	0.560	1
FAM98B	physical association	0.560	1
GLP1R	physical association	0.510	2
PB2	association	0.430	1
POLR2A	physical association	0.400	1
YWHAZ	physical association	0.400	1
DNAJB6	association	0.350	1
DISC1	physical association	0.000	2
PCNT	physical association	0.000	1

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
tRNA splicing ligase	6	FAM98B, RTCB, RTRAF, ZBTB8OS, C2orf49, DDX1
tRNA Splicing Ligase Complex	5	C2orf49, DDX1, FAM98B, RTCB, RTRAF

Disease & clinical

Genetic variants

Variant evidence for RTRAF: 16 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

16 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 406):

Position(s)	Effect	Δscore	Sites
14:51989701	donor_loss	1.0000	2
14:51991312	acceptor_gain	1.0000
14:51991315–51991316	acceptor_loss	1.0000	2
14:51991442–51991443	donor_loss	1.0000	4
14:51993720	acceptor_gain	1.0000
14:51993721–51993722	acceptor_loss	1.0000	6
14:51993823–51993824	donor_loss	1.0000	5
14:51998492–51998493	acceptor_loss	1.0000	5
14:51998581–51998582	donor_loss	1.0000	5
14:52004354	acceptor_gain	1.0000

AlphaMissense

986 missense substitutions predicted likely pathogenic (of 1,622 scored), across 200 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D34	8	0.998	1.000
D236	8	0.996	1.000
N220	8	0.993	1.000
D194	8	0.985	0.996
F190	8	0.981	0.999
D94	8	0.978	0.998
H208	8	0.977	0.999
H146	8	0.972	0.994
F130	8	0.957	0.995
D232	8	0.955	0.997
D81	8	0.954	0.989
F17	8	0.895	0.994
D191	8	0.872	0.967
D66	8	0.866	0.950
D129	8	0.861	0.968
H12	8	0.846	0.989
R38	7	0.999	1.000
W31	7	0.998	1.000
E33	7	0.997	0.999
W56	7	0.996	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000122
Lung Adenocarcinoma (TCGA)	unfavorable	0.000576

Disease associations

OMIM: gene MIM:610858 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST004412_11	Craniofacial microsomia	1e-7

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067445 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, decreases methylation	3
Cyclosporine	increases expression	2
2,4,6-tribromophenol	decreases expression	1
arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	decreases expression	1
chloropicrin	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Aminoglutethimide	decreases expression	1
Arsenic	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Josamycin	affects response to substance	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652876	Binding	Binding affinity to human C14orf166 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for RTRAF across ~30M SureChEMBL compounds — explore on Sugi Predict.