UPF3B

Summary

UPF3B (UPF3B regulator of nonsense mediated mRNA decay, HGNC:20439) is a protein-coding gene on chromosome Xq24, encoding Regulator of nonsense transcripts 3B (Q9BZI7). Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. The encoded protein is one of two functional homologs to yeast Upf3p. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions. This gene is located on the long arm of chromosome X. Two splice variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 65109 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 430 total — 24 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 50
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_080632

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20439
Approved symbol	UPF3B
Name	UPF3B regulator of nonsense mediated mRNA decay
Location	Xq24
Locus type	gene with protein product
Status	Approved
Aliases	RENT3B, UPF3X, HUPF3B, MRX82
Ensembl gene	ENSG00000125351
Ensembl biotype	protein_coding
OMIM	300298
Entrez	65109

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 retained_intron

ENST00000276201, ENST00000345865, ENST00000478840, ENST00000887634, ENST00000887635, ENST00000938427, ENST00000938428, ENST00000938429, ENST00000938430, ENST00000938431, ENST00000951330

RefSeq mRNA: 2 — MANE Select: NM_080632 NM_023010, NM_080632

CCDS: CCDS14587, CCDS14588

Canonical transcript exons

ENST00000276201 — 11 exons

Exon	Start	End
ENSE00000000363	119852773	119852963
ENSE00000854492	119837757	119838051
ENSE00000854496	119845198	119845296
ENSE00000854497	119851495	119851601
ENSE00000854498	119851767	119851873
ENSE00000979319	119840646	119840684
ENSE00000979322	119838367	119838527
ENSE00001848175	119834022	119835027
ENSE00003573957	119841076	119841258
ENSE00003622011	119843191	119843301
ENSE00003666702	119841735	119841778

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 96.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.2482 / max 502.3765, expressed in 1719 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200319	12.3970	1710
200315	0.3917	125
200312	0.3524	155
200317	0.3160	123
200311	0.3110	141
200310	0.3074	127
200318	0.1727	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.04	gold quality
esophagus squamous epithelium	UBERON:0006920	90.26	gold quality
embryo	UBERON:0000922	89.53	gold quality
cerebellar hemisphere	UBERON:0002245	89.39	gold quality
cerebellar cortex	UBERON:0002129	89.38	gold quality
ganglionic eminence	UBERON:0004023	89.38	gold quality
endothelial cell	CL:0000115	89.19	gold quality
amniotic fluid	UBERON:0000173	89.17	gold quality
cerebellum	UBERON:0002037	88.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.66	gold quality
ventricular zone	UBERON:0003053	88.53	gold quality
cortical plate	UBERON:0005343	88.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.86	gold quality
visceral pleura	UBERON:0002401	87.33	gold quality
pleura	UBERON:0000977	86.96	gold quality
monocyte	CL:0000576	86.59	gold quality
epithelium of nasopharynx	UBERON:0001951	86.56	gold quality
nasopharynx	UBERON:0001728	86.54	gold quality
parietal pleura	UBERON:0002400	86.50	gold quality
squamous epithelium	UBERON:0006914	86.47	gold quality
cerebellar vermis	UBERON:0004720	86.43	gold quality
mononuclear cell	CL:0000842	86.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.38	gold quality
lower esophagus mucosa	UBERON:0035834	86.19	gold quality
epithelium of esophagus	UBERON:0001976	85.97	gold quality
leukocyte	CL:0000738	85.88	gold quality
right uterine tube	UBERON:0001302	85.73	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.39	gold quality
calcaneal tendon	UBERON:0003701	85.14	gold quality
adenohypophysis	UBERON:0002196	85.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SATB2

miRNA regulators (miRDB)

50 targeting UPF3B, 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-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-5000-3P	98.79	65.63	1251

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 25)

• binds to spliced mRNAs upstream of exon-exon junctions; is part of mRNP complexes that are ready for nuclear export and that participate in nonsense-mediated mRNA decay (PMID:11546873)
• binds RNPS1 protein, part of the postsplicing complex deposited 5’ to exon-exon junctions (PMID:11546874)
• A conserved domain of hUpf3b mediates an interaction with the EJC protein Y14. Y14 is required for nonsense-mediated decay induced by tethered hUpf3b. (PMID:12718880)
• The protein region that mediates this interaction and discriminates between hUpf3a and hUpf3b in NMD function is located in the C-terminal domain and fully contained within a small sequence that is highly conserved in Upf3b but not Upf3a proteins (PMID:16601204)
• UPF3B induces nonsense mediated decay in the cytoplasm (PMID:17194930)
• Three mutations lead to the introduction of a premature termination codon and subsequent nonsense-mediated mRNA decay of mutant UPF3B mRNA. (PMID:17704778)
• UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1. (PMID:18066079)
• Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. (PMID:19238151)
• Results suggest that UPF3A levels are tightly regulated by a post-transcriptional switch to maintain appropriate levels of NMD substrates in cells containing different levels of UPF3B. (PMID:19503078)
• 3.4 A resolution crystal structure of a minimal UPF3b-EJC assembly, consisting of the interacting domains of five proteins (UPF3b, MAGO, Y14, eIF4AIII, and Barentsz) together with RNA and adenylyl-imidodiphosphate (PMID:20479275)
• results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells. (PMID:22182939)
• The two cases with renal dysplasia and developmental delay showed remarkable clinical variability despite having the same mutation in UPF3B. (PMID:22609145)
• Data indicate the mutation p.R430X of UPF3B gene as the genetic etiology in the mental retardation pedigree. (PMID:22957832)
• These findings indicate that SATB2 activates UPF3B expression through binding to its promoter. (PMID:23925499)
• the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of nonsense-mediated mRNA decay pathway function altering neuronal differentiation. (PMID:26012578)
• UPF3B gene mutation is associated with Lujan-Fryns syndrome. (PMID:26358559)
• The authors discovered that UPF3B (i) interacts with the release factors, (ii) delays translation termination and (iii) dissociates post-termination ribosomal complexes that are devoid of the nascent peptide. (PMID:28899899)
• RNAseq studies reveal that depletion of ICE1 globally enhances accumulation and stability of NMD-target mRNAs. Further, our data suggest that ICE1 uses a putative MIF4G domain to interact with exon junction complex (EJC) proteins and promotes the association of the NMD protein UPF3B with the EJC. (PMID:29528287)
• A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks. (PMID:32667670)
• Human UPF3A and UPF3B enable fault-tolerant activation of nonsense-mediated mRNA decay. (PMID:35451084)
• Mammalian UPF3A and UPF3B can activate nonsense-mediated mRNA decay independently of their exon junction complex binding. (PMID:35451102)
• Structures of nonsense-mediated mRNA decay factors UPF3B and UPF3A in complex with UPF2 reveal molecular basis for competitive binding and for neurodevelopmental disorder-causing mutation. (PMID:35640974)
• Up-Frameshift Suppressor 3 as a prognostic biomarker and correlated with immune infiltrates: A pan-cancer analysis. (PMID:36194583)
• Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients. (PMID:37797718)
• Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target. (PMID:38889220)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	upf3b	ENSDARG00000000489
mus_musculus	Upf3b	ENSMUSG00000036572
rattus_norvegicus	Upf3b	ENSRNOG00000039994
drosophila_melanogaster	Upf3	FBGN0034923
caenorhabditis_elegans		WBGENE00004882

Paralogs (1): UPF3A (ENSG00000169062)

Protein

Protein identifiers

Regulator of nonsense transcripts 3B — Q9BZI7 (reviewed: Q9BZI7)

Alternative names: Nonsense mRNA reducing factor 3B, Up-frameshift suppressor 3 homolog B, Up-frameshift suppressor 3 homolog on chromosome X

All UniProt accessions (1): Q9BZI7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery. Recruits UPF2 at the cytoplasmic side of the nuclear envelope and the subsequent formation of an UPF1-UPF2-UPF3 surveillance complex (including UPF1 bound to release factors at the stalled ribosome) is believed to activate NMD. In cooperation with UPF2 stimulates both ATPase and RNA helicase activities of UPF1. Binds spliced mRNA upstream of exon-exon junctions. In vitro, stimulates translation; the function is independent of association with UPF2 and components of the EJC core.

Subunit / interactions. Found in a post-splicing messenger ribonucleoprotein (mRNP) complex. Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A. The EJC core components EIF4A3 and the MAGOH-RBM8A dimer form a composite binding site for UPF3B which overlaps with the EJC binding site for WIBG. Interacts with EST1A, UPF2 and RBM8A. Interacts with CPSF6. Interacts with DHX34; the interaction is RNA-independent.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in testis, uterus, prostate, heart, muscle, brain, spinal cord and placenta.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic 14 (MRXS14) [MIM:300676] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXS14 patients manifest intellectual disability associated with other variable signs such as autistic features, slender build, poor musculature, long, thin face, high-arched palate, high nasal bridge, and pectus deformities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RENT3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BZI7-1	1	yes
Q9BZI7-2	2

RefSeq proteins (2): NP_075386, NP_542199* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005120	UPF3_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034979	UPF3B_RRM-like	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR039722	Upf3	Family

Pfam: PF03467

UniProt features (49 total): mutagenesis site 16, compositionally biased region 7, region of interest 6, strand 6, modified residue 4, helix 4, turn 2, chain 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1UW4	X-RAY DIFFRACTION	1.95
7NWU	X-RAY DIFFRACTION	2.6
2XB2	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZI7-F1	67.35	0.19

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 (4): 169, 198, 310, 447

Mutagenesis-validated functional residues (16):

Position	Phenotype
52	abolishes interaction with upf2.
53–58	abolishes interaction with upf2.
56	does not abolish interaction with upf2.
117–119	abolishes interaction with upf2.
430	reduces nmd.
432	reduces nmd.
434–447	abolishes nmd.
434	reduces nmd.
435	reduces nmd.
436	impairs association with ejc.
436	reduces nmd.
441	reduces nmd.
442	impairs association with ejc.
447	abolishes nmd; when associated with e-449 and e-451.
449	abolishes nmd; when associated with e-447 and e-451.
451	abolishes nmd; when associated with e-447 and e-449.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72187	mRNA 3’-end processing
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-73856	RNA Polymerase II Transcription Termination

MSigDB gene sets: 264 (showing top): GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, GOBP_POSITIVE_REGULATION_OF_MRNA_PROCESSING, AAGTCCA_MIR422B_MIR422A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, YY1_Q6, GOBP_TRANSLATION, GTGCCTT_MIR506, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, YY1_02, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, GOBP_RNA_SPLICING, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP

GO Biological Process (8): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), brain development (GO:0007420), neuron projection development (GO:0031175), positive regulation of neuron differentiation (GO:0045666), positive regulation of translation (GO:0045727), mRNA transport (GO:0051028), random inactivation of X chromosome (GO:0060816), positive regulation of mRNA cis splicing, via spliceosome (GO:1905746)

GO Molecular Function (4): RNA binding (GO:0003723), mRNA binding (GO:0003729), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), centriolar satellite (GO:0034451), exon-exon junction complex (GO:0035145), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Transport of Mature Transcript to Cytoplasm	1
mRNA Splicing	1
Processing of Capped Intron-Containing Pre-mRNA	1
Signaling by ROBO receptors	1
Nonsense-Mediated Decay (NMD)	1
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	2
nuclear lumen	2
nuclear-transcribed mRNA catabolic process	1
central nervous system development	1
animal organ development	1
head development	1
neuron development	1
plasma membrane bounded cell projection organization	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
translation	1
regulation of translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
RNA transport	1
dosage compensation by inactivation of X chromosome	1
mRNA cis splicing, via spliceosome	1
positive regulation of mRNA splicing, via spliceosome	1
regulation of mRNA cis splicing, via spliceosome	1
nucleic acid binding	1
RNA binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
centrosome	1
nuclear protein-containing complex	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

1404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UPF3B	UPF2	Q9HAU5	999
UPF3B	UPF1	Q92900	995
UPF3B	EIF4A3	P38919	991
UPF3B	MAGOH	P50606	965
UPF3B	MAGOHB	Q96A72	962
UPF3B	SMG5	Q9UPR3	934
UPF3B	RBM8A	Q9Y5S9	931
UPF3B	RNPS1	Q15287	922
UPF3B	SMG7	Q92540	917
UPF3B	SMG1	Q96Q15	906
UPF3B	ALYREF	Q86V81	878
UPF3B	STAU1	O95793	871
UPF3B	SMG6	Q86US8	864
UPF3B	SMG8	Q8ND04	838
UPF3B	NCBP1	Q09161	824

IntAct

80 interactions, top by confidence:

A	B	Type	Score
CASC3	EIF4A3	psi-mi:“MI:0914”(association)	0.980
EIF4A3	CASC3	psi-mi:“MI:0914”(association)	0.980
MAGOH	CASC3	psi-mi:“MI:0914”(association)	0.970
UPF2	UPF1	psi-mi:“MI:0914”(association)	0.960
EIF4A3	MAGOH	psi-mi:“MI:0914”(association)	0.940
RBM8A	UPF3B	psi-mi:“MI:0915”(physical association)	0.910
UPF3B	RBM8A	psi-mi:“MI:0915”(physical association)	0.910
UPF3B	UPF2	psi-mi:“MI:0915”(physical association)	0.900
UPF2	UPF3B	psi-mi:“MI:0915”(physical association)	0.900
RBM8A	CASC3	psi-mi:“MI:0914”(association)	0.900
UPF2	UPF3B	psi-mi:“MI:0914”(association)	0.900
UPF1	UPF3B	psi-mi:“MI:0914”(association)	0.890
UPF3B	UPF1	psi-mi:“MI:0915”(physical association)	0.890
UPF1	UPF3B	psi-mi:“MI:0915”(physical association)	0.890
EIF4A3	UPF3B	psi-mi:“MI:0915”(physical association)	0.880
MAGOH	UPF3B	psi-mi:“MI:0915”(physical association)	0.770
UPF1	CASC3	psi-mi:“MI:0914”(association)	0.770
UPF3B	MAGOH	psi-mi:“MI:0914”(association)	0.770
SMG1	UPF1	psi-mi:“MI:0914”(association)	0.760
RBM8A	UPF1	psi-mi:“MI:0914”(association)	0.730
SMG1	EIF4A3	psi-mi:“MI:0914”(association)	0.690
UPF3B	CASC3	psi-mi:“MI:0914”(association)	0.640
UPF3B	RNPS1	psi-mi:“MI:0914”(association)	0.640

BioGRID (193): UPF3B (Affinity Capture-Western), UPF3B (Affinity Capture-Western), UPF3B (Affinity Capture-MS), UPF3B (Affinity Capture-MS), UPF3B (Affinity Capture-MS), EIF4A3 (Reconstituted Complex), CASC3 (Reconstituted Complex), MAGOH (Reconstituted Complex), RBM8A (Reconstituted Complex), MEPCE (Co-fractionation), UPF3B (Co-fractionation), UPF3B (Co-fractionation), UPF3B (Proximity Label-MS), UPF3B (Biochemical Activity), UPF3B (Affinity Capture-MS)

ESM2 similar proteins: A2AJT4, A2CG63, B0S733, F1QNX7, G3V8T1, O75376, O94988, P29536, Q02040, Q14241, Q149C2, Q15695, Q15696, Q28G87, Q2KIC0, Q4FZU3, Q4G0J3, Q4KKX4, Q4LE39, Q4R627, Q53F19, Q561R3, Q5NCR9, Q5R4U2, Q5RL73, Q5U2T3, Q5XIN3, Q5ZM19, Q60974, Q62377, Q63187, Q64707, Q6PFK1, Q6PGZ3, Q8BZR9, Q8C761, Q8CB77, Q8K2X2, Q8QG78, Q8TDR0

Diamond homologs: B0S733, F1QNX7, Q10267, Q9BZI7, Q9FVW4, Q9H1J1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SATB2	“up-regulates quantity by expression”	UPF3B	“transcriptional regulation”
UPF3B	“form complex”	Upf-EJC	binding
UPF3B	“up-regulates activity”	UPF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 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
mRNA 3’-end processing	8	33.5×	6e-09
Nonsense-Mediated Decay (NMD)	6	29.8×	3e-06
Transport of Mature mRNA derived from an Intron-Containing Transcript	9	29.2×	3e-09
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	13	27.0×	3e-13
Regulation of expression of SLITs and ROBOs	11	16.2×	5e-09
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	6	15.0×	1e-04
mRNA Splicing	6	14.0×	1e-04
Signaling by ROBO receptors	5	13.2×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	10	91.8×	3e-15
mRNA export from nucleus	10	58.0×	2e-13
regulation of alternative mRNA splicing, via spliceosome	6	28.7×	5e-06
negative regulation of translation	5	19.2×	3e-04
mRNA splicing, via spliceosome	10	18.0×	3e-08
RNA splicing	8	13.8×	8e-06
translation	5	10.1×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	13
Uncertain significance	132
Likely benign	102
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11399	NM_080632.3(UPF3B):c.867_868del (p.Gly290fs)	Pathogenic
11400	NM_080632.3(UPF3B):c.1288C>T (p.Arg430Ter)	Pathogenic
11401	NM_080632.3(UPF3B):c.478T>G (p.Tyr160Asp)	Pathogenic
1199884	NM_080632.3(UPF3B):c.684_687del (p.Arg229fs)	Pathogenic
1275792	NM_080632.3(UPF3B):c.684_685del (p.Glu230fs)	Pathogenic
1323743	NM_080632.3(UPF3B):c.670G>T (p.Glu224Ter)	Pathogenic
1699417	NM_080632.3(UPF3B):c.1166_1167del (p.Lys389fs)	Pathogenic
198608	NM_080632.3(UPF3B):c.674_677del (p.Arg225fs)	Pathogenic
2092837	NM_080632.3(UPF3B):c.160delinsAC (p.Val54fs)	Pathogenic
2430487	NM_080632.3(UPF3B):c.1091_1094del (p.Glu364fs)	Pathogenic
2430883	NM_080632.3(UPF3B):c.1157_1158del (p.Thr385_Phe386insTer)	Pathogenic
2446159	NM_080632.3(UPF3B):c.159_160delinsTAC (p.Val54fs)	Pathogenic
3186789	NM_080632.3(UPF3B):c.16G>T (p.Glu6Ter)	Pathogenic
3255086	NM_080632.3(UPF3B):c.442_443del (p.Asp148fs)	Pathogenic
3600688	NM_080632.3(UPF3B):c.724C>T (p.Arg242Ter)	Pathogenic
4076027	GRCh37/hg19 Xq24(chrX:118964526-118979535)x0	Pathogenic
420043	NM_080632.3(UPF3B):c.697_698del (p.Arg233fs)	Pathogenic
429957	NM_080632.3(UPF3B):c.690_697del (p.Arg233fs)	Pathogenic
4685508	NM_080632.3(UPF3B):c.280_283del (p.Tyr94fs)	Pathogenic
4814224	NM_080632.3(UPF3B):c.617_620del (p.Asn206fs)	Pathogenic
488634	NM_080632.3(UPF3B):c.1351del (p.Arg451fs)	Pathogenic
624437	NM_080632.3(UPF3B):c.2_3insA (p.Met1fs)	Pathogenic
807522	NM_080632.3(UPF3B):c.575_578del (p.Glu191_Leu192insTer)	Pathogenic
871633	NM_080632.3(UPF3B):c.1149_1150del (p.Lys384fs)	Pathogenic
1325336	NM_080632.3(UPF3B):c.982G>T (p.Glu328Ter)	Likely pathogenic
1712323	NM_080632.3(UPF3B):c.270T>G (p.Tyr90Ter)	Likely pathogenic
1804141	NM_080632.3(UPF3B):c.1147G>T (p.Glu383Ter)	Likely pathogenic
3027439	NM_080632.3(UPF3B):c.240del (p.Phe80fs)	Likely pathogenic
3336985	NM_080632.3(UPF3B):c.1266_1269del (p.Glu423fs)	Likely pathogenic
3384385	NM_080632.3(UPF3B):c.37C>T (p.Arg13Ter)	Likely pathogenic

SpliceAI

1348 predictions. Top by Δscore:

Variant	Effect	Δscore
X:119835023:CGATC:C	acceptor_gain	1.0000
X:119835025:ATCC:A	acceptor_loss	1.0000
X:119835026:TC:T	acceptor_gain	1.0000
X:119835027:CC:C	acceptor_gain	1.0000
X:119835027:CCTGA:C	acceptor_loss	1.0000
X:119835028:C:CC	acceptor_gain	1.0000
X:119837751:CAGCA:C	donor_loss	1.0000
X:119837753:GCAC:G	donor_loss	1.0000
X:119837754:CA:C	donor_loss	1.0000
X:119837756:C:T	donor_loss	1.0000
X:119838363:TGA:T	donor_loss	1.0000
X:119838364:GAC:G	donor_loss	1.0000
X:119838366:CCT:C	donor_gain	1.0000
X:119838525:CAG:C	acceptor_gain	1.0000
X:119838528:C:CC	acceptor_gain	1.0000
X:119838529:T:C	acceptor_gain	1.0000
X:119838530:T:C	acceptor_gain	1.0000
X:119838530:T:TC	acceptor_gain	1.0000
X:119841150:T:A	donor_gain	1.0000
X:119841255:TTCT:T	acceptor_gain	1.0000
X:119843311:CATT:C	acceptor_gain	1.0000
X:119843314:T:C	acceptor_gain	1.0000
X:119843314:T:TC	acceptor_gain	1.0000
X:119845191:A:AC	donor_gain	1.0000
X:119845192:C:CC	donor_gain	1.0000
X:119851489:ACTC:A	donor_loss	1.0000
X:119851490:CTCA:C	donor_loss	1.0000
X:119851491:TCA:T	donor_loss	1.0000
X:119851492:CAC:C	donor_loss	1.0000
X:119851493:A:C	donor_loss	1.0000

AlphaMissense

3231 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:119834996:C:T	G445E	1.000
X:119834999:G:T	P444Q	1.000
X:119835000:G:A	P444S	1.000
X:119835005:T:C	Y442C	1.000
X:119835006:A:C	Y442D	1.000
X:119835006:A:G	Y442H	1.000
X:119835006:A:T	Y442N	1.000
X:119835008:A:T	L441H	1.000
X:119835014:A:G	M439T	1.000
X:119835020:G:T	P437Q	1.000
X:119835021:G:A	P437S	1.000
X:119835021:G:T	P437T	1.000
X:119835023:C:T	R436H	1.000
X:119835024:G:A	R436C	1.000
X:119835024:G:C	R436G	1.000
X:119835024:G:T	R436S	1.000
X:119835026:T:A	D435V	1.000
X:119835026:T:G	D435A	1.000
X:119835027:C:G	D435H	1.000
X:119837757:C:A	K434N	1.000
X:119837757:C:G	K434N	1.000
X:119837758:T:A	K434M	1.000
X:119837759:T:C	K434E	1.000
X:119837760:G:C	N433K	1.000
X:119837760:G:T	N433K	1.000
X:119837763:T:A	R432S	1.000
X:119837763:T:G	R432S	1.000
X:119837764:C:A	R432I	1.000
X:119837764:C:G	R432T	1.000
X:119841184:C:A	R233S	1.000

dbSNP variants (sampled 300 via entrez): RS1000098972 (X:119808355 C>G,T), RS1000157000 (X:119850833 G>A), RS1000270682 (X:119850558 A>C), RS1000272529 (X:119820406 C>T), RS1000281035 (X:119807968 A>C), RS1000367430 (X:119842588 A>T), RS1000418809 (X:119808870 CTCTT>C), RS1000492346 (X:119852975 G>A), RS1000717762 (X:119844881 G>A), RS1000805502 (X:119821049 T>C), RS1000819515 (X:119843791 A>G), RS1000843516 (X:119812163 G>T), RS1000854493 (X:119835158 G>A,T), RS1000876346 (X:119824550 G>C,T), RS1000907598 (X:119826476 C>T)

Disease associations

OMIM: gene MIM:300298 | disease phenotypes: MIM:300676, MIM:116200

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability 14	Definitive	X-linked
X-linked intellectual disability with marfanoid habitus	Supportive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (7): syndromic X-linked intellectual disability 14 (MONDO:0010398), neurodevelopmental disorder (MONDO:0700092), microcephaly (MONDO:0001149), cataract (MONDO:0005129), intellectual disability (MONDO:0001071), X-linked intellectual disability with marfanoid habitus (MONDO:0010655), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (2): Lujan-Fryns syndrome (Orphanet:776), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000053	Macroorchidism
HP:0000098	Tall stature
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000678	Dental crowding
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000729	Autistic behavior
HP:0000738	Hallucinations
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000774	Narrow chest
HP:0001156	Brachydactyly
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
C537724	Lujan Fryns syndrome (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)
C567063	Mental Retardation, X-Linked, Syndromic 14 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	4
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1
cobaltous chloride	increases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
versicolorin A	increases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
jasplakinolide	affects localization, affects binding, decreases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, decreases expression	1
Caffeine	increases phosphorylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2NG	HAP1 UPF3B (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice