RNGTT

Summary

RNGTT (RNA guanylyltransferase and 5’-phosphatase, HGNC:10073) is a protein-coding gene on chromosome 6q15, encoding mRNA-capping enzyme (O60942). Bifunctional mRNA-capping enzyme exhibiting RNA 5’-triphosphate monophosphatase activity in the N-terminal part and mRNA guanylyltransferase activity in the C-terminal part. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Enables inorganic triphosphate phosphatase activity and mRNA guanylyltransferase activity. Involved in 7-methylguanosine mRNA capping. Predicted to be located in nucleoplasm.

Source: NCBI Gene 8732 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 77 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_003800

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10073
Approved symbol	RNGTT
Name	RNA guanylyltransferase and 5’-phosphatase
Location	6q15
Locus type	gene with protein product
Status	Approved
Aliases	HCE, HCE1, hCAP
Ensembl gene	ENSG00000111880
Ensembl biotype	protein_coding
OMIM	603512
Entrez	8732

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 retained_intron

ENST00000369475, ENST00000369485, ENST00000538899, ENST00000627296, ENST00000871524, ENST00000923815, ENST00000923816, ENST00000923817, ENST00000923818, ENST00000961643

RefSeq mRNA: 3 — MANE Select: NM_003800 NM_001286426, NM_001286428, NM_003800

CCDS: CCDS5017, CCDS69153

Canonical transcript exons

ENST00000369485 — 16 exons

Exon	Start	End
ENSE00000760350	88614272	88614395
ENSE00000760351	88678353	88678419
ENSE00000760352	88769774	88769874
ENSE00000760353	88801564	88801632
ENSE00000760354	88844357	88844521
ENSE00000760355	88849755	88849826
ENSE00000760356	88853629	88853764
ENSE00000798180	88904715	88904955
ENSE00000798181	88928985	88929073
ENSE00000918693	88890495	88890596
ENSE00000918694	88891806	88891915
ENSE00000918695	88906365	88906440
ENSE00001823083	88609897	88612882
ENSE00001829011	88963346	88963618
ENSE00002526802	88941071	88941180
ENSE00003732933	88929164	88929267

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 94.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.7076 / max 401.6199, expressed in 1805 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74658	18.4305	1804
74657	0.2771	141

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cardia of stomach	UBERON:0001162	94.50	silver quality
nipple	UBERON:0002030	94.31	gold quality
pylorus	UBERON:0001166	93.70	gold quality
superior surface of tongue	UBERON:0007371	93.18	gold quality
pharyngeal mucosa	UBERON:0000355	92.62	gold quality
ventral tegmental area	UBERON:0002691	92.55	silver quality
subthalamic nucleus	UBERON:0001906	91.95	silver quality
inferior vagus X ganglion	UBERON:0005363	91.87	silver quality
vena cava	UBERON:0004087	91.58	silver quality
renal medulla	UBERON:0000362	91.43	gold quality
trigeminal ganglion	UBERON:0001675	91.14	gold quality
body of tongue	UBERON:0011876	91.03	silver quality
superior vestibular nucleus	UBERON:0007227	91.01	gold quality
pericardium	UBERON:0002407	90.84	silver quality
tongue	UBERON:0001723	90.57	gold quality
saphenous vein	UBERON:0007318	90.32	silver quality
epithelium of nasopharynx	UBERON:0001951	90.18	silver quality
lateral globus pallidus	UBERON:0002476	90.01	gold quality
sperm	CL:0000019	89.65	gold quality
medulla oblongata	UBERON:0001896	89.65	silver quality
dorsal plus ventral thalamus	UBERON:0001897	89.42	silver quality
substantia nigra pars reticulata	UBERON:0001966	89.42	gold quality
dorsal root ganglion	UBERON:0000044	89.38	silver quality
penis	UBERON:0000989	89.27	gold quality
pons	UBERON:0000988	89.17	silver quality
substantia nigra pars compacta	UBERON:0001965	88.79	silver quality
male germ cell	CL:0000015	88.51	gold quality
corpus callosum	UBERON:0002336	88.24	gold quality
urethra	UBERON:0000057	86.95	gold quality
synovial joint	UBERON:0002217	86.77	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP63

miRNA regulators (miRDB)

146 targeting RNGTT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• Data show that human capping enzyme residues 229-567 comprise the minimum enzymatically active human GTase (hGTase) domain and determine the structure by X-ray crystallography. (PMID:21636784)
• Our biochemical studies provide the first insight that MZP can inhibit the formation of the RNA cap structure catalyzed by HCE. (PMID:23349942)
• These results identify a new domain of CE that is specific to its function in cytoplasmic capping, and a new role for Nck1 in regulating gene expression through its role as the scaffold for assembly of the cytoplasmic capping complex. (PMID:25137142)
• c-Myc deregulation induces mRNA capping enzyme dependency in tumor cells. (PMID:27756891)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rngtt	ENSDARG00000032261
mus_musculus	Rngtt	ENSMUSG00000028274
rattus_norvegicus	Rngtt	ENSRNOG00000007867
drosophila_melanogaster	mRNA-cap	FBGN0030556
caenorhabditis_elegans	cel-1	WBGENE00000466

Paralogs (1): DUSP11 (ENSG00000144048)

Protein

Protein identifiers

mRNA-capping enzyme — O60942 (reviewed: O60942)

Alternative names: HCAP1, HCE

All UniProt accessions (1): O60942

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional mRNA-capping enzyme exhibiting RNA 5’-triphosphate monophosphatase activity in the N-terminal part and mRNA guanylyltransferase activity in the C-terminal part. Catalyzes the first two steps of cap formation: by removing the gamma-phosphate from the 5’-triphosphate end of nascent mRNA to yield a diphosphate end, and by transferring the GMP moiety of GTP to the 5’-diphosphate terminus of RNA via a covalent enzyme-GMP reaction intermediate.

Subunit / interactions. Interacts with POLR2A (via C-terminus); this enhances guanylyltransferase activity. Binds (via GTase domain) to the elongating phosphorylated form of RNA polymerase II; can form direct interactions with the phosphorylated POLR2A C-terminal domain and indirect interactions via bound RNA. Interacts with SUPT5H and RNMT. Interacts with HIV-1 Tat. (Microbial infection) Interacts with HIV-1 Tat.

Subcellular location. Nucleus.

Tissue specificity. Isoform 1 and isoform 4 (at a lesser extent) are expressed in cerebrum, cerebellum, thyroid, lung, heart, liver, kidney, spleen, large intestine, testis, skin and muscle.

Miscellaneous. Isoform 2 to isoform 4 lack mRNA 5’-guanylyltransferase activity due to disruptions of the GTase domain.

Similarity. In the N-terminal section; belongs to the non-receptor class of the protein-tyrosine phosphatase family. In the C-terminal section; belongs to the eukaryotic GTase family.

Isoforms (4)

UniProt ID	Names	Canonical?
O60942-1	1, HCE1, HCAP1A	yes
O60942-2	2, HCE1A
O60942-3	3, HCE1B
O60942-4	4, HCAP1B

RefSeq proteins (3): NP_001273355, NP_001273357, NP_003791* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000340	Dual-sp_phosphatase_cat-dom	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR001339	mRNA_cap_enzyme_adenylation	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR013846	mRNA_cap_enzyme_C	Domain
IPR016130	Tyr_Pase_AS	Active_site
IPR017074	mRNA_cap_enz_bifunc	Family
IPR020422	TYR_PHOSPHATASE_DUAL_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR051029

Pfam: PF00782, PF01331, PF03919

Enzyme classification (BRENDA):

• EC 2.7.7.50 — mRNA guanylyltransferase (BRENDA: 27 organisms, 148 substrates, 43 inhibitors, 22 Km, 4 kcat entries)
• EC 3.6.1.74 — mRNA 5’-phosphatase (BRENDA: 7 organisms, 37 substrates, 14 inhibitors, 4 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0011–0.017	6
PP(5’)APGP	0.0003	2
PP(5’)GCC(A2,U2G)N	0.0005–0.004	2
RNA	0.0003	2
DIPHOSPHATE	2	1
DIPHOSPHATE TERMINATED POLY(A) WITH AN AVERAGE C	0.019	1
DIPHOSPHATE-ENDED POLY(A)	—	1
LAMBDAC17RNA	0.0001	1
PP(5’)A(PA)N	—	1
TERMINI OF 5’-TRIPHOSPHATE POLY(A)	0.0002	1
A 5’-TRIPHOSPHO-[MRNA]	0.003	1
PPPA-TERMINATED POLY(A)	0.0014	1

Catalyzed reactions (Rhea), 2 shown:

• a 5’-end triphospho-ribonucleoside in mRNA + H2O = a 5’-end diphospho-ribonucleoside in mRNA + phosphate + H(+) (RHEA:67004)
• a 5’-end diphospho-ribonucleoside in mRNA + GTP + H(+) = a 5’-end (5’-triphosphoguanosine)-ribonucleoside in mRNA + diphosphate (RHEA:67012)

UniProt features (81 total): strand 25, helix 19, mutagenesis site 10, binding site 5, region of interest 5, turn 5, splice variant 3, sequence conflict 3, active site 2, chain 1, domain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2C46	X-RAY DIFFRACTION	1.6
3S24	X-RAY DIFFRACTION	3.01
8P4B	ELECTRON MICROSCOPY	3.2
8P4A	ELECTRON MICROSCOPY	3.6
8P4D	ELECTRON MICROSCOPY	3.6
8P4C	ELECTRON MICROSCOPY	3.8
8P4E	ELECTRON MICROSCOPY	3.9
8W8E	ELECTRON MICROSCOPY	3.9
8W8F	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60942-F1	85.78	0.63

Functional residue map

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

Catalytic / active sites (2): 126 (phosphocysteine intermediate); 294 (n6-gmp-lysine intermediate)

Ligand- & substrate-binding residues (5): 299; 315; 343–345; 458–460; 528–533

Mutagenesis-validated functional residues (10):

Position	Phenotype
234	no effect on gtase activity.
294	loss of gtase activity.
299	loss of gtase activity.
345	loss of gtase activity.
458	loss of gtase activity.
460	loss of gtase activity.
528	strongly reduced gtase activity.
530	loss of gtase activity.
532	loss of gtase activity.
533	loss of gtase activity.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-167160	RNA Pol II CTD phosphorylation and interaction with CE during HIV infection
R-HSA-72086	mRNA Capping
R-HSA-77075	RNA Pol II CTD phosphorylation and interaction with CE
R-HSA-162587	HIV Life Cycle
R-HSA-162599	Late Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-1643685	Disease
R-HSA-167172	Transcription of the HIV genome
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953854	Metabolism of RNA
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 194 (showing top): chr6q15, MODULE_97, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_182, MITSIADES_RESPONSE_TO_APLIDIN_DN, TGACCTY_ERR1_Q2, REACTOME_HIV_INFECTION, BLALOCK_ALZHEIMERS_DISEASE_UP, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP, GOBP_RNA_CAPPING, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, ACATTCC_MIR1_MIR206, LIU_CMYB_TARGETS_UP, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (6): 7-methylguanosine mRNA capping (GO:0006370), RNA processing (GO:0006396), nucleobase-containing compound metabolic process (GO:0006139), mRNA processing (GO:0006397), protein dephosphorylation (GO:0006470), dephosphorylation (GO:0016311)

GO Molecular Function (14): mRNA guanylyltransferase activity (GO:0004484), polynucleotide 5’-phosphatase activity (GO:0004651), phosphoprotein phosphatase activity (GO:0004721), ATP binding (GO:0005524), GTP binding (GO:0005525), RNA guanylyltransferase activity (GO:0008192), inorganic triphosphate phosphatase activity (GO:0050355), mRNA 5’-triphosphate monophosphatase activity (GO:0140818), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), hydrolase activity (GO:0016787)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Transcription of the HIV genome	1
Metabolism of RNA	1
RNA Polymerase II Transcription	1
HIV Infection	1
HIV Life Cycle	1
Viral Infection Pathways	1
Late Phase of HIV Life Cycle	1
Disease	1
Gene expression (Transcription)	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	2
phosphatase activity	2
purine ribonucleoside triphosphate binding	2
catalytic activity, acting on RNA	2
pyrophosphatase activity	2
catalytic activity	2
mRNA processing	1
7-methylguanosine RNA capping	1
gene expression	1
RNA biosynthetic process	1
RNA processing	1
mRNA metabolic process	1
dephosphorylation	1
protein modification process	1
phosphate-containing compound metabolic process	1
RNA guanylyltransferase activity	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
guanylyltransferase activity	1
polynucleotide 5’-phosphatase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1998 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNGTT	RNMT	O43148	981
RNGTT	CLEC14A	Q86T13	928
RNGTT	CES1	P23141	798
RNGTT	CMTR1	Q8N1G2	747
RNGTT	PMP22	Q01453	718
RNGTT	SUPT5H	O00267	714
RNGTT	CMTR2	Q8IYT2	690
RNGTT	RAMAC	Q9BTL3	647
RNGTT	TYMP	P19971	576
RNGTT	NCK1	P16333	557
RNGTT	MTMR4	Q9NYA4	523
RNGTT	NCBP2	P52298	510
RNGTT	SH2D3A	Q9BRG2	507
RNGTT	EIF4E	P06730	504
RNGTT	TGS1	Q96RS0	494

IntAct

45 interactions, top by confidence:

A	B	Type	Score
NUP50	KPNA4	psi-mi:“MI:0914”(association)	0.830
POLR2D	MED19	psi-mi:“MI:0914”(association)	0.730
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
RNGTT	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
RNGTT	KPNA2	psi-mi:“MI:0915”(physical association)	0.560
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
SV2A	EXTL3	psi-mi:“MI:0914”(association)	0.530
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430
NCK1	RNGTT	psi-mi:“MI:0915”(physical association)	0.400
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
INTU	PSMD12	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SH3GL3	RBFOX3	psi-mi:“MI:0914”(association)	0.350
POLR2M	MED19	psi-mi:“MI:0914”(association)	0.350
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
RNGTT	SUPT5H	psi-mi:“MI:0914”(association)	0.350
IRAK1	ILVBL	psi-mi:“MI:0914”(association)	0.350
CTDP1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
KPNA4	POM121C	psi-mi:“MI:0914”(association)	0.350
RAN	NUP214	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
EEF1D	VWA8	psi-mi:“MI:0914”(association)	0.350
KPNA5	SPOP	psi-mi:“MI:0914”(association)	0.350
TIMM50	ZNF320	psi-mi:“MI:0914”(association)	0.350

BioGRID (190): RNGTT (Affinity Capture-MS), RNGTT (Affinity Capture-MS), RNGTT (Affinity Capture-MS), RNGTT (Affinity Capture-MS), POLR2A (Affinity Capture-MS), POLR2B (Affinity Capture-MS), POLR2C (Affinity Capture-MS), POLR2D (Affinity Capture-MS), POLR2E (Affinity Capture-MS), POLR2G (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4R2 (Affinity Capture-MS), SMEK1 (Affinity Capture-MS), SMEK2 (Affinity Capture-MS), SUPT5H (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KTI4, A0A7U2QYM2, O00763, O55236, O60942, P10687, P10894, P29074, P48722, P55014, P55015, P91926, P97789, Q03330, Q07722, Q13621, Q15147, Q28BT8, Q28EX9, Q28GH3, Q29N38, Q338B9, Q4V7N2, Q59WH0, Q641F1, Q642Q1, Q66HV4, Q6DI37, Q6H8D6, Q6NY98, Q6YXZ7, Q756G9, Q7QG73, Q7SXG4, Q7ZVX6, Q7ZY60, Q8BPM2, Q8C878, Q8WZM0, Q924I2

Diamond homologs: O10274, O55236, O60942, O75319, P24656, P34442, Q17607, Q22707, Q4KM79, Q5E999, Q6NXK5, Q6NY98, Q6NT99, Q9BVJ7, Q9P7H1, Q6PFY9, Q6CWR0, A1L1R5, A2A3K4, A7E379, O60729, P81299, Q4JDL3, Q4QEZ7, Q5B323, Q6NZK8, Q8JHZ8, Q9ULE6, Q9ZQP1, A4D256, P70261

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RNGTT	“up-regulates quantity”	mRNA_capping	“chemical modification”
RNGTT	“up-regulates quantity”	“messenger RNA”	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NS1 Mediated Effects on Host Pathways	8	47.6×	2e-09
Transport of Ribonucleoproteins into the Host Nucleus	5	37.2×	2e-05
Nuclear import of Rev protein	5	35.0×	2e-05
ISG15 antiviral mechanism	8	25.0×	2e-07
Antimicrobial mechanism of IFN-stimulated genes	6	24.6×	2e-05
Maturation of DENV proteins	5	22.0×	1e-04
Influenza Infection	6	22.0×	2e-05
Interferon Signaling	6	15.0×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
NLS-bearing protein import into nucleus	5	71.7×	2e-06
protein import into nucleus	9	23.1×	8e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4698 predictions. Top by Δscore:

Variant	Effect	Δscore
6:88612878:CACAG:C	acceptor_gain	1.0000
6:88612879:ACAG:A	acceptor_gain	1.0000
6:88612880:CAG:C	acceptor_gain	1.0000
6:88612880:CAGC:C	acceptor_gain	1.0000
6:88612881:AG:A	acceptor_gain	1.0000
6:88612883:C:CC	acceptor_gain	1.0000
6:88612883:C:CG	acceptor_loss	1.0000
6:88612884:T:A	acceptor_loss	1.0000
6:88612890:C:CT	acceptor_gain	1.0000
6:88614266:A:AC	donor_gain	1.0000
6:88614267:C:CC	donor_gain	1.0000
6:88614269:CA:C	donor_loss	1.0000
6:88614270:A:AC	donor_gain	1.0000
6:88614270:A:C	donor_loss	1.0000
6:88614270:AC:A	donor_gain	1.0000
6:88614270:ACC:A	donor_gain	1.0000
6:88614271:C:A	donor_loss	1.0000
6:88614271:C:CA	donor_gain	1.0000
6:88614271:CC:C	donor_gain	1.0000
6:88614271:CCC:C	donor_gain	1.0000
6:88614271:CCCA:C	donor_gain	1.0000
6:88614271:CCCAT:C	donor_gain	1.0000
6:88614391:GTCAC:G	acceptor_gain	1.0000
6:88614392:TCAC:T	acceptor_gain	1.0000
6:88614393:CAC:C	acceptor_gain	1.0000
6:88614393:CACC:C	acceptor_gain	1.0000
6:88614394:AC:A	acceptor_gain	1.0000
6:88614395:CCTGT:C	acceptor_gain	1.0000
6:88614396:C:CA	acceptor_loss	1.0000
6:88614396:C:CC	acceptor_gain	1.0000

AlphaMissense

3965 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:88612855:A:T	V553D	1.000
6:88614291:A:C	N537K	1.000
6:88614291:A:T	N537K	1.000
6:88614303:T:A	K533N	1.000
6:88614303:T:G	K533N	1.000
6:88614304:T:A	K533I	1.000
6:88614305:T:C	K533E	1.000
6:88614305:T:G	K533Q	1.000
6:88614312:T:A	R530S	1.000
6:88614312:T:G	R530S	1.000
6:88614313:C:G	R530T	1.000
6:88614332:A:G	W524R	1.000
6:88614332:A:T	W524R	1.000
6:88614353:A:G	C517R	1.000
6:88769801:A:G	L471P	1.000
6:88769806:A:C	F469L	1.000
6:88769806:A:T	F469L	1.000
6:88769808:A:G	F469L	1.000
6:88769809:A:C	D468E	1.000
6:88769809:A:T	D468E	1.000
6:88769810:T:A	D468V	1.000
6:88769810:T:C	D468G	1.000
6:88769811:C:G	D468H	1.000
6:88769838:A:G	W459R	1.000
6:88769838:A:T	W459R	1.000
6:88769839:T:A	K458N	1.000
6:88769839:T:G	K458N	1.000
6:88769841:T:C	K458E	1.000
6:88801586:C:T	G439E	1.000
6:88844387:C:A	K413N	1.000

dbSNP variants (sampled 300 via entrez): RS1000016428 (6:88802588 C>A,T), RS1000018652 (6:88670863 G>A), RS1000022189 (6:88758949 T>C), RS1000032045 (6:88899480 G>A), RS1000045443 (6:88629541 T>G), RS1000049241 (6:88943183 C>T), RS1000063405 (6:88680085 A>G), RS1000065406 (6:88714571 T>A,C), RS1000067323 (6:88665430 C>T), RS1000076553 (6:88639173 C>A), RS1000089053 (6:88708235 T>G), RS1000090216 (6:88892010 T>A,C,G), RS1000094470 (6:88823558 C>A), RS1000096904 (6:88801930 A>C), RS1000097074 (6:88935662 T>C)

Disease associations

OMIM: gene MIM:603512 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000635_30	Response to statin therapy	1.000000e-06
GCST001521_35	Subcutaneous adipose tissue	8.000000e-06
GCST003209_3	Colorectal or endometrial cancer	2.000000e-07
GCST006427_49	Depression in smokers	2.000000e-07
GCST008551_14	Simvastatin-induced myopathy	9.000000e-06
GCST008839_573	Height	3.000000e-09
GCST010683_1	Graft survival time in renal transplantation (donor effect)	6.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004230	endometrial neoplasm
EFO:0005199	renal transplant outcome measurement
EFO:0007892	donor genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724645 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178522: Inhibition of RNGTT (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.3000	uM

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
geldanamycin	increases expression, decreases expression	2
Cisplatin	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
monorden	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone	decreases expression	1
Sunitinib	increases expression	1
Arsenic	increases expression, increases abundance	1
Atrazine	decreases expression	1
Manganese	increases abundance, increases expression	1
Mercury	affects expression	1
Methapyrilene	decreases methylation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697252	Binding	Inhibition of RNGTT (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.