RLIM

Summary

RLIM (ring finger protein, LIM domain interacting, HGNC:13429) is a protein-coding gene on chromosome Xq13.2, encoding E3 ubiquitin-protein ligase RLIM (Q9NVW2). E3 ubiquitin-protein ligase that acts as a negative coregulator for LIM homeodomain transcription factors by mediating the ubiquitination and subsequent degradation of LIM cofactors LDB1 and LDB2 and by mediating the recruitment the SIN3a/histone deacetylase corepressor complex.

The protein encoded by this gene is a RING-H2 zinc finger protein. It has been shown to be an E3 ubiquitin protein ligase that targets LIM domain binding 1 (LDB1/CLIM), and causes proteasome-dependent degradation of LDB1. This protein and LDB1 are co-repressors of LHX1/LIM-1, a homeodomain transcription factor. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 51132 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 185 total — 3 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 51
• MANE Select transcript: NM_016120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13429
Approved symbol	RLIM
Name	ring finger protein, LIM domain interacting
Location	Xq13.2
Locus type	gene with protein product
Status	Approved
Aliases	NY-REN-43, MGC15161
Ensembl gene	ENSG00000131263
Ensembl biotype	protein_coding
OMIM	300379
Entrez	51132

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000332687, ENST00000349225, ENST00000896517, ENST00000896518, ENST00000896519, ENST00000896520, ENST00000921461, ENST00000958909, ENST00000958910

RefSeq mRNA: 2 — MANE Select: NM_016120 NM_016120, NM_183353

CCDS: CCDS14427

Canonical transcript exons

ENST00000332687 — 4 exons

Exon	Start	End
ENSE00000899028	74595809	74596000
ENSE00000899030	74594306	74594389
ENSE00001848246	74582976	74593061
ENSE00003888963	74614422	74614624

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 94.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9906 / max 229.6578, expressed in 1750 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199771	6.7735	1674
199770	3.5881	1332
199768	0.8694	417
199769	0.6176	328
199767	0.1420	59

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	94.13	gold quality
cartilage tissue	UBERON:0002418	93.71	gold quality
adrenal tissue	UBERON:0018303	93.09	gold quality
calcaneal tendon	UBERON:0003701	93.02	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.82	gold quality
postcentral gyrus	UBERON:0002581	92.78	gold quality
tendon	UBERON:0000043	92.57	gold quality
medial globus pallidus	UBERON:0002477	92.39	gold quality
entorhinal cortex	UBERON:0002728	92.37	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.31	gold quality
tendon of biceps brachii	UBERON:0008188	91.99	gold quality
parietal lobe	UBERON:0001872	91.73	gold quality
substantia nigra pars compacta	UBERON:0001965	91.72	gold quality
superior frontal gyrus	UBERON:0002661	91.68	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.53	gold quality
left ventricle myocardium	UBERON:0006566	91.37	gold quality
tibia	UBERON:0000979	91.06	gold quality
globus pallidus	UBERON:0001875	90.22	gold quality
upper arm skin	UBERON:0004263	90.20	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.09	gold quality
esophagus squamous epithelium	UBERON:0006920	89.71	gold quality
caput epididymis	UBERON:0004358	89.36	gold quality
deltoid	UBERON:0001476	89.28	gold quality
kidney epithelium	UBERON:0004819	89.25	gold quality
superficial temporal artery	UBERON:0001614	89.24	gold quality
epithelial cell of pancreas	CL:0000083	89.22	gold quality
cauda epididymis	UBERON:0004360	89.22	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.07	gold quality
cortical plate	UBERON:0005343	88.91	gold quality
corpus epididymis	UBERON:0004359	88.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, NANOG, POU5F1, SOX2, SP1, TP53, ZFP42

miRNA regulators (miRDB)

364 targeting RLIM, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 21)

• Functional analysis of the Xenopus homolog (PMID:12874135)
• RLIM represents a new pathway for telomere maintenance by modulating the level of TRF1 at telomeres. (PMID:19164295)
• These findings provide evidence for a dose-dependent role of RNF12 in the XCI counting and initiation process. (PMID:19945382)
• these results indicated that RLIM is an important positive regulator in TGF-beta signaling pathway and cell migration. (PMID:21945933)
• TP53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter. (PMID:23650532)
• hus regulated nucleocytoplasmic shuttling of RLIM/Rnf12 coordinates cellular compartments during mammary alveolar cell survival (PMID:23904271)
• Rlim is a novel regulator of Stathmin protein in a ubiquitin-dependent manner, and represents a new pathway for malignant phenotype turnover by modulating the level of Stathmin protein in human osteosarcomas. (PMID:24686088)
• missense mutation in RLIM gene was identified in four males with intellectual disability from a three-generation family. (PMID:25735484)
• Results from a study on gene expression variability markers in early-stage human embryos shows that RLIM is a putative expression variability marker for the 3-day, 8-cell embryo stage. (PMID:26288249)
• RNF12 is a novel positive regulator of p53 pathway and an external E3 ubiquitin ligase for MDM2 destruction. (PMID:26926424)
• These data uncover a key function for RNF12 E3 ubiquitin ligase activity in stem cell and neural development. (PMID:29742418)
• These findings uncover a novel mechanism for the regulation of BRF1 and reveal RNF12 as an important regulator of Pol III-dependent transcription. (PMID:30413534)
• Kaposi’s Sarcoma-Associated Herpesvirus LANA Modulates the Stability of the E3 Ubiquitin Ligase RLIM. (PMID:31801865)
• The RING Domain of RING Finger 12 Efficiently Builds Degradative Ubiquitin Chains. (PMID:32416094)
• RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features. (PMID:33159883)
• A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome. (PMID:33953269)
• RNF12 is regulated by AKT phosphorylation and promotes TGF-beta driven breast cancer metastasis. (PMID:35013159)
• Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression. (PMID:35040952)
• An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations. (PMID:35857630)
• Ring finger protein 12 activates AKT signalling to promote the progression of liver cancer by interacting with EGFR. (PMID:37132043)
• How does the Xist activator Rlim/Rnf12 regulate Xist expression? (PMID:38747697)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rlim	ENSDARG00000079306
mus_musculus	Rlim	ENSMUSG00000056537
rattus_norvegicus	Rlim	ENSRNOG00000045695

Paralogs (3): RNF6 (ENSG00000127870), RNF38 (ENSG00000137075), RNF44 (ENSG00000146083)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RLIM — Q9NVW2 (reviewed: Q9NVW2)

Alternative names: LIM domain-interacting RING finger protein, RING finger LIM domain-binding protein, RING finger protein 12, RING-type E3 ubiquitin transferase RLIM, Renal carcinoma antigen NY-REN-43

All UniProt accessions (1): Q9NVW2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that acts as a negative coregulator for LIM homeodomain transcription factors by mediating the ubiquitination and subsequent degradation of LIM cofactors LDB1 and LDB2 and by mediating the recruitment the SIN3a/histone deacetylase corepressor complex. Ubiquitination and degradation of LIM cofactors LDB1 and LDB2 allows DNA-bound LIM homeodomain transcription factors to interact with other protein partners such as RLIM. Plays a role in telomere length-mediated growth suppression by mediating the ubiquitination and degradation of TERF1. By targeting ZFP42/REX1 for degradation, acts as an activator of random inactivation of X chromosome in the embryo, a stochastic process in which one X chromosome is inactivated to minimize sex-related dosage differences of X-encoded genes in somatic cells of female placental mammals. E3 ubiquitin-protein ligase is required for proper regulation of neural cell differentiation from embryonic stem cells.

Subunit / interactions. Forms homodimers. Interacts with LIM/homeobox factors such as LHX3. Interacts with LDB1, LDB2 and SIN3A. Interacts with LIMK1. Interacts (via N-terminus) with TERF1. Interacts (via C-terminus) with ESR1.

Subcellular location. Nucleus.

Tissue specificity. Expressed in many tissues.

Disease relevance. Tonne-Kalscheuer syndrome (TOKAS) [MIM:300978] An X-linked recessive disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, abnormal gait, dysmorphic facial features, limb anomalies, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death. Carrier females may have very mild skeletal or hormonal abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Acts as a positive coregulator of ESR1-mediated transcription in breast cancer cells.

Similarity. Belongs to the RNF12 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NVW2-1	1	yes
Q9NVW2-2	2

RefSeq proteins (2): NP_057204, NP_899196 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR051834	RING_finger_E3_ligase	Family
IPR058896	RNF6/12_N	Domain

Pfam: PF13639, PF25914

UniProt features (52 total): sequence variant 14, compositionally biased region 10, modified residue 6, region of interest 5, sequence conflict 4, helix 3, strand 3, splice variant 2, turn 2, chain 1, zinc finger region 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6W7Z	X-RAY DIFFRACTION	1.8
6W9A	X-RAY DIFFRACTION	2.3
6W9D	X-RAY DIFFRACTION	3.19

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVW2-F1	50.55	0.08

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 (6): 1, 164, 195, 228, 230, 276

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 325 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, CCAWYNNGAAR_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, RORA1_01, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, TTTGTAG_MIR520D, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GGGTGGRR_PAX4_03, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), negative regulation of DNA-templated transcription (GO:0045892), regulation of neurogenesis (GO:0050767), random inactivation of X chromosome (GO:0060816)

GO Molecular Function (6): transcription corepressor activity (GO:0003714), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), transcription repressor complex (GO:0017053)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of DNA-templated transcription	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
dosage compensation by inactivation of X chromosome	1
transcription coregulator activity	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
transcription regulator complex	1

Protein interactions and networks

STRING

1519 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RLIM	AXIN2	Q9Y2T1	913
RLIM	LDB1	Q86U70	785
RLIM	LHX2	P50458	726
RLIM	LHX3	Q9UBR4	702
RLIM	CHIC1	Q5VXU3	690
RLIM	LHX1	P48742	647
RLIM	LDB2	O43679	644
RLIM	NANOG	Q9H9S0	631
RLIM	NEXMIF	Q5QGS0	616
RLIM	POU5F1	P31359	608
RLIM	UBE2H	P37286	608
RLIM	SMAD7	O15105	607
RLIM	SMURF2	Q9HAU4	589
RLIM	ISL1	P20663	577
RLIM	SOX2	P48431	577

IntAct

88 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
NFIB	NFIC	psi-mi:“MI:0914”(association)	0.690
NFIC	NFIB	psi-mi:“MI:0914”(association)	0.690
NFIA	NFIB	psi-mi:“MI:0914”(association)	0.570
APBA2	HERC2	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
ANTXR1	WFS1	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
TOLLIP	IRAK2	psi-mi:“MI:0914”(association)	0.500
LDB2	RLIM	psi-mi:“MI:0407”(direct interaction)	0.500
LDB2	RLIM	psi-mi:“MI:0220”(ubiquitination reaction)	0.500
RLIM	DLG1	psi-mi:“MI:0915”(physical association)	0.400
RLIM	UPF3B	psi-mi:“MI:0915”(physical association)	0.400
	RLIM	psi-mi:“MI:0915”(physical association)	0.400
RLIM	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.400
UBE2O	RLIM	psi-mi:“MI:0915”(physical association)	0.400
RLIM		psi-mi:“MI:0915”(physical association)	0.370
UBE2D1	RLIM	psi-mi:“MI:0915”(physical association)	0.370
RLIM	UBE2D2	psi-mi:“MI:0915”(physical association)	0.370
RLIM	UBE2D3	psi-mi:“MI:0915”(physical association)	0.370
RLIM	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
RLIM	UBE2E2	psi-mi:“MI:0915”(physical association)	0.370
UBE2D4	RLIM	psi-mi:“MI:0915”(physical association)	0.370
SS18L1	RLIM	psi-mi:“MI:0915”(physical association)	0.370
STAT6	RLIM	psi-mi:“MI:0915”(physical association)	0.370
RPS14	RLIM	psi-mi:“MI:0915”(physical association)	0.370
RLIM	SNX17	psi-mi:“MI:0915”(physical association)	0.370
RLIM	LNX2	psi-mi:“MI:0915”(physical association)	0.370
UBXN1	PJA2	psi-mi:“MI:0914”(association)	0.350
DNAJB2	UBB	psi-mi:“MI:0914”(association)	0.350

BioGRID (452): RLIM (Affinity Capture-RNA), RLIM (Affinity Capture-Western), RLIM (Affinity Capture-Western), STMN1 (Affinity Capture-Western), RLIM (Affinity Capture-Western), RLIM (Affinity Capture-MS), MDM2 (Affinity Capture-Western), MDM2 (Reconstituted Complex), RLIM (Reconstituted Complex), MDM2 (Biochemical Activity), UBE2D1 (Reconstituted Complex), RLIM (Affinity Capture-MS), RLIM (Affinity Capture-MS), RLIM (Affinity Capture-MS), UPF3B (Affinity Capture-MS)

ESM2 similar proteins: A1CBG9, A1DDX0, A2AH22, A2RA63, B0Y1D1, B3P4M4, B4KCG1, B8NKS1, E7FAG6, O42631, O42967, O94400, P10240, P14349, P28990, P32828, P34256, P34675, P84445, P87237, P87311, Q07G42, Q0CW83, Q0V9R0, Q2U685, Q48B61, Q4WVI6, Q4ZMD6, Q5R9W2, Q5XI50, Q641J8, Q66J97, Q6NRV8, Q87039, Q8BI21, Q8RK09, Q8RK12, Q90ZT7, Q9C0C7, Q9DBU5

Diamond homologs: A5WWA0, E9QAU8, G3X9R7, O22197, O22755, O43567, O54965, O64763, P0C034, P0CH30, P0DPR2, Q06003, Q07G42, Q08D68, Q0II22, Q0VD51, Q10R93, Q14B02, Q29RU0, Q2TA44, Q3U2C5, Q4KLR8, Q4R6Y5, Q5NCP0, Q5RCV8, Q5RF74, Q5SPX3, Q5SSZ7, Q5XF85, Q641J8, Q66HG0, Q68DV7, Q69U49, Q6AY01, Q6DIP3, Q6IRP0, Q6NML0, Q6NQG7, Q6NRX0, Q6Y290

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RLIM	ubiquitination
RLIM	“down-regulates quantity by destabilization”	MYC	ubiquitination
SP1	“up-regulates quantity by expression”	RLIM	“transcriptional regulation”
TP53	“down-regulates quantity by repression”	RLIM	“transcriptional regulation”
RLIM	“down-regulates quantity by destabilization”	ZFP42	ubiquitination
RLIM	“down-regulates quantity by destabilization”	LDB2	polyubiquitination
RLIM	“down-regulates quantity by destabilization”	LDB1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
TICAM1, RIP1-mediated IKK complex recruitment	5	35.4×	1e-04
IKK complex recruitment mediated by RIP1	5	29.2×	2e-04
Negative regulators of DDX58/IFIH1 signaling	5	19.2×	9e-04
Regulation of TNFR1 signaling	5	13.2×	4e-03
E3 ubiquitin ligases ubiquitinate target proteins	5	11.4×	6e-03
Antigen processing: Ubiquitination & Proteasome degradation	12	5.2×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	5	14.8×	6e-03
protein K48-linked ubiquitination	9	13.1×	1e-05
proteasome-mediated ubiquitin-dependent protein catabolic process	15	6.8×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	6
Uncertain significance	109
Likely benign	26
Benign	4

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
156224	NM_016120.4(RLIM):c.1067A>G (p.Tyr356Cys)	Pathogenic
253087	NM_016120.4(RLIM):c.1760C>G (p.Pro587Arg)	Pathogenic
253089	NM_016120.4(RLIM):c.1795C>T (p.Arg599Cys)	Pathogenic
1098327	NM_016120.4(RLIM):c.366G>C (p.Trp122Cys)	Likely pathogenic
1184531	NM_016120.4(RLIM):c.992G>A (p.Gly331Glu)	Likely pathogenic
585245	NM_016120.4(RLIM):c.1831C>T (p.Arg611Cys)	Likely pathogenic
598940	NM_016120.4(RLIM):c.1729T>C (p.Tyr577His)	Likely pathogenic
633533	NM_016120.4(RLIM):c.659G>A (p.Arg220Lys)	Likely pathogenic
979167	NM_016120.4(RLIM):c.1262A>G (p.Tyr421Cys)	Likely pathogenic

SpliceAI

772 predictions. Top by Δscore:

Variant	Effect	Δscore
X:74594301:CATA:C	donor_loss	1.0000
X:74594302:ATAC:A	donor_loss	1.0000
X:74594303:TAC:T	donor_loss	1.0000
X:74594304:A:AC	donor_gain	1.0000
X:74594304:AC:A	donor_gain	1.0000
X:74594304:ACCT:A	donor_gain	1.0000
X:74594305:C:CA	donor_loss	1.0000
X:74594305:C:CC	donor_gain	1.0000
X:74594305:CC:C	donor_gain	1.0000
X:74594305:CCT:C	donor_gain	1.0000
X:74594305:CCTC:C	donor_gain	1.0000
X:74594305:CCTCT:C	donor_gain	1.0000
X:74594385:TTCAC:T	acceptor_gain	1.0000
X:74594386:TCAC:T	acceptor_gain	1.0000
X:74594387:CAC:C	acceptor_gain	1.0000
X:74594387:CACC:C	acceptor_gain	1.0000
X:74594388:AC:A	acceptor_gain	1.0000
X:74594389:CC:C	acceptor_gain	1.0000
X:74594390:C:CA	acceptor_loss	1.0000
X:74594390:C:CC	acceptor_gain	1.0000
X:74594395:A:AC	acceptor_gain	1.0000
X:74594396:T:TC	acceptor_gain	1.0000
X:74594397:T:C	acceptor_gain	1.0000
X:74594397:T:TC	acceptor_gain	1.0000
X:74594404:C:CT	acceptor_gain	1.0000
X:74595805:ATACC:A	donor_loss	1.0000
X:74595806:TACCT:T	donor_loss	1.0000
X:74595807:ACCTG:A	donor_loss	1.0000
X:74595808:CCTG:C	donor_loss	1.0000
X:74595838:ATAAG:A	donor_gain	1.0000

AlphaMissense

4070 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:74591484:G:T	R611S	1.000
X:74591485:A:C	C610W	1.000
X:74591486:C:A	C610F	1.000
X:74591486:C:G	C610S	1.000
X:74591486:C:T	C610Y	1.000
X:74591487:A:G	C610R	1.000
X:74591487:A:T	C610S	1.000
X:74591492:G:C	P608R	1.000
X:74591492:G:T	P608H	1.000
X:74591493:G:A	P608S	1.000
X:74591493:G:T	P608T	1.000
X:74591494:A:C	C607W	1.000
X:74591495:C:A	C607F	1.000
X:74591495:C:G	C607S	1.000
X:74591495:C:T	C607Y	1.000
X:74591496:A:C	C607G	1.000
X:74591496:A:G	C607R	1.000
X:74591496:A:T	C607S	1.000
X:74591513:A:G	L601S	1.000
X:74591515:C:A	W600C	1.000
X:74591515:C:G	W600C	1.000
X:74591516:C:G	W600S	1.000
X:74591517:A:C	W600G	1.000
X:74591517:A:G	W600R	1.000
X:74591517:A:T	W600R	1.000
X:74591522:T:A	D598V	1.000
X:74591522:T:G	D598A	1.000
X:74591523:C:A	D598Y	1.000
X:74591523:C:G	D598H	1.000
X:74591525:A:C	I597S	1.000

dbSNP variants (sampled 300 via entrez): RS1000093109 (X:74610145 G>A), RS1000171188 (X:74597552 A>G), RS1000316395 (X:74607944 T>C), RS1000348839 (X:74607565 C>T), RS1000507335 (X:74596209 G>A), RS1000541957 (X:74603199 C>G,T), RS1000543012 (X:74597837 T>C), RS1000702180 (X:74611854 T>C), RS1000766303 (X:74613885 G>A), RS1000923789 (X:74588874 G>C), RS1000955967 (X:74588483 C>CAAAA), RS1001051092 (X:74612172 A>G,T), RS1001155992 (X:74599930 T>G), RS1001323305 (X:74610143 G>A), RS1001355847 (X:74609881 T>C)

Disease associations

OMIM: gene MIM:300379 | disease phenotypes: MIM:300978, MIM:309530, MIM:213300

GenCC curated gene-disease

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	X-linked
intellectual disability, X-linked 61	Strong	X-linked
syndromic intellectual disability	Supportive	Autosomal dominant

Mondo (5): intellectual disability, X-linked 61 (MONDO:0010506), non-syndromic X-linked intellectual disability (MONDO:0019181), prostate cancer (MONDO:0008315), Joubert syndrome (MONDO:0018772), syndromic intellectual disability (MONDO:0000508)

Orphanet (3): X-linked non-syndromic intellectual disability (Orphanet:777), Familial prostate cancer (Orphanet:1331), Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000160	Narrow mouth
HP:0000220	Velopharyngeal insufficiency
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000275	Narrow face
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000448	Prominent nose
HP:0000494	Downslanted palpebral fissures
HP:0000601	Hypotelorism
HP:0000635	Blue irides
HP:0000687	Widely spaced teeth
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000776	Congenital diaphragmatic hernia
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90017147_1	Brain asymmetrical skew (horizontal)	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression	3
trichostatin A	affects expression, increases expression	2
Estradiol	affects expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cupric oxide	increases expression	1
resorcinol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
PCI 5002	increases expression, affects cotreatment	1
Irinotecan	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	increases expression	1
Benzo(a)pyrene	affects methylation	1
Formaldehyde	decreases expression	1
Nickel	increases expression	1
Oxazolone	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Plant Oils	increases expression	1
Vitamin E	decreases expression	1
Zinc	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TJ13	HAP1 RLIM (-) 1	Cancer cell line	Male
CVCL_TJ14	HAP1 RLIM (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer