NBEA

Summary

NBEA (neurobeachin, HGNC:7648) is a protein-coding gene on chromosome 13q13.3, encoding Neurobeachin (Q8NFP9). Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the membrane. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of a large, diverse group of A-kinase anchor proteins that target the activity of protein kinase A to specific subcellular sites by binding to its type II regulatory subunits. Brain-specific expression and coat protein-like membrane recruitment of a highly similar protein in mouse suggest an involvement in neuronal post-Golgi membrane traffic. Mutations in this gene may be associated with a form of autism. This gene and its expression are frequently disrupted in patients with multiple myeloma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants may exist, but their full-length nature has not been determined.

Source: NCBI Gene 26960 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 922 total — 35 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 22
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 11 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001385012

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7648
Approved symbol	NBEA
Name	neurobeachin
Location	13q13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1544, BCL8B, FLJ10197, LYST2
Ensembl gene	ENSG00000172915
Ensembl biotype	protein_coding
OMIM	604889
Entrez	26960

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 25 protein_coding, 15 retained_intron, 12 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay

ENST00000379922, ENST00000379939, ENST00000400445, ENST00000461581, ENST00000497540, ENST00000537702, ENST00000629018, ENST00000685025, ENST00000685163, ENST00000685329, ENST00000685686, ENST00000685717, ENST00000685987, ENST00000685991, ENST00000686320, ENST00000686386, ENST00000686647, ENST00000686669, ENST00000686741, ENST00000686952, ENST00000686972, ENST00000687287, ENST00000687587, ENST00000687732, ENST00000687868, ENST00000687952, ENST00000688053, ENST00000688312, ENST00000688335, ENST00000688363, ENST00000688422, ENST00000688626, ENST00000689079, ENST00000689207, ENST00000689454, ENST00000689568, ENST00000689818, ENST00000690273, ENST00000690712, ENST00000690972, ENST00000690976, ENST00000691097, ENST00000691196, ENST00000691351, ENST00000691561, ENST00000691637, ENST00000692196, ENST00000692238, ENST00000692464, ENST00000692578, ENST00000692628, ENST00000692737, ENST00000693034, ENST00000693205, ENST00000693262, ENST00000693547, ENST00000693712, ENST00000693735

RefSeq mRNA: 4 — MANE Select: NM_001385012 NM_001204197, NM_001379245, NM_001385012, NM_015678

CCDS: CCDS45026, CCDS55894, CCDS91801

Canonical transcript exons

ENST00000379939 — 59 exons

Exon	Start	End
ENSE00000817062	35646259	35646348
ENSE00000938858	35654855	35655010
ENSE00000938859	35655579	35655749
ENSE00000938861	35667374	35667570
ENSE00001093038	35171272	35171452
ENSE00001285208	35649655	35649847
ENSE00001285746	35668368	35668519
ENSE00001285764	35665085	35665186
ENSE00001285783	35651805	35651876
ENSE00001369525	35645869	35645931
ENSE00001483114	35670901	35672736
ENSE00001483255	35164356	35164509
ENSE00001596242	35048563	35048684
ENSE00001599744	35208700	35208854
ENSE00001604367	35040933	35041164
ENSE00001606244	35110810	35110978
ENSE00001617230	35044947	35045047
ENSE00001623961	35069908	35070105
ENSE00001628436	35045306	35045401
ENSE00001631716	35183976	35184071
ENSE00001632619	35050269	35050395
ENSE00001638980	35593328	35593447
ENSE00001640038	35583898	35584038
ENSE00001648177	35195864	35196302
ENSE00001652091	35123482	35123574
ENSE00001660809	35161750	35161967
ENSE00001665411	35349108	35349216
ENSE00001666195	35211053	35211179
ENSE00001678406	35176996	35177103
ENSE00001687681	35118377	35118474
ENSE00001693067	35452092	35452235
ENSE00001694286	35173464	35173594
ENSE00001697764	35117414	35117493
ENSE00001698962	35156083	35156206
ENSE00001700531	35070719	35070852
ENSE00001705300	35290389	35290450
ENSE00001710491	35550930	35551032
ENSE00001712465	35157078	35157270
ENSE00001719886	35432269	35432393
ENSE00001725002	35566905	35567017
ENSE00001725063	35109290	35109442
ENSE00001735748	35142269	35142377
ENSE00001736656	35182360	35182528
ENSE00001736958	35628081	35628248
ENSE00001737878	35155774	35155855
ENSE00001738284	35118228	35118290
ENSE00001739929	35098297	35098405
ENSE00001750561	35309528	35309592
ENSE00001760697	35159016	35160032
ENSE00001769363	35056010	35056129
ENSE00001775070	35232492	35232619
ENSE00001776405	35554987	35555102
ENSE00001781062	35058717	35058863
ENSE00001788293	35472400	35472536
ENSE00001788989	35352157	35352323
ENSE00001792523	35168987	35168995
ENSE00002704235	34942270	34943114
ENSE00003579259	35606426	35606578
ENSE00003607157	35550477	35550594

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 98.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6165 / max 244.0114, expressed in 1199 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134740	7.9901	1158
134753	0.1601	70
134752	0.1245	47
134754	0.0911	26
134747	0.0795	28
134748	0.0615	15
134749	0.0552	20
134755	0.0545	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.44	gold quality
pigmented layer of retina	UBERON:0001782	97.29	gold quality
pons	UBERON:0000988	96.54	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.03	gold quality
bronchial epithelial cell	CL:0002328	95.10	gold quality
cerebellar vermis	UBERON:0004720	95.10	gold quality
middle temporal gyrus	UBERON:0002771	94.79	gold quality
epithelium of bronchus	UBERON:0002031	93.69	gold quality
endothelial cell	CL:0000115	93.53	gold quality
orbitofrontal cortex	UBERON:0004167	93.40	gold quality
bronchus	UBERON:0002185	93.18	gold quality
primary visual cortex	UBERON:0002436	92.16	gold quality
occipital lobe	UBERON:0002021	92.03	gold quality
parietal lobe	UBERON:0001872	92.02	gold quality
superior frontal gyrus	UBERON:0002661	91.90	gold quality
postcentral gyrus	UBERON:0002581	91.69	gold quality
cerebellum	UBERON:0002037	91.64	gold quality
entorhinal cortex	UBERON:0002728	91.61	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.61	gold quality
cerebellar cortex	UBERON:0002129	91.34	gold quality
cerebellar hemisphere	UBERON:0002245	91.23	gold quality
superior vestibular nucleus	UBERON:0007227	90.83	gold quality
ganglionic eminence	UBERON:0004023	90.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.47	gold quality
prefrontal cortex	UBERON:0000451	89.82	gold quality
frontal cortex	UBERON:0001870	89.39	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.24	gold quality
urethra	UBERON:0000057	88.87	gold quality
neocortex	UBERON:0001950	88.77	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.66	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	75.94
E-HCAD-5	yes	45.87
E-ANND-3	yes	7.66
E-CURD-135	no	788.55
E-GEOD-111727	no	561.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

247 targeting NBEA, 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-98-3P	100.00	74.08	3907
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-4455	100.00	65.48	1587
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 10)

• Structural analysis and biochemical studies show that the PH and BEACH domains have strong interactions, suggesting they may function as a single unit. (PMID:12234919)
• neurobeachin encoding gene is disrupted in a patient with a de novo translocation t(5;13) (q12.1;q13.2), idiopathic autism, and no family history of autism (PMID:12746398)
• The NBEA gene at 13q13, and its expression are frequently disrupted in MM. (PMID:19135901)
• data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits (PMID:22438821)
• Synapse associated protein 102 (SAP102) binds the C-terminal part of the scaffolding protein neurobeachin. (PMID:22745750)
• Data indicate that the PVT1-NBEA and the PVT1-WWOX chimeric genes were associated with the expression of abnormal NBEA and WWOX. (PMID:22869583)
• NBEA encodes neurobeachin: we found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder. (PMID:25451450)
• We identified 24 de novo NBEA variants in patients with neurodevelopmental disease, establishing NBEA as an neurodevelopmental disease gene (PMID:30269351)
• Our study suggests that rs180940944 (NBEA) is associated with an increased Non-muscle-invasive Bladder Cancer tumour size at the time of diagnosis (PMID:31277774)
• Familial paroxysmal kinesigenic dyskinesia with a novel missense variant (Arg2866Trp) in NBEA. (PMID:33692494)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nbeaa	ENSDARG00000070080
danio_rerio	nbeab	ENSDARG00000105184
mus_musculus	Nbea	ENSMUSG00000027799
rattus_norvegicus	Nbea	ENSRNOG00000065312
caenorhabditis_elegans		WBGENE00004760
caenorhabditis_elegans		WBGENE00007752

Paralogs (7): NSMAF (ENSG00000035681), WDFY4 (ENSG00000128815), LYST (ENSG00000143669), NBEAL1 (ENSG00000144426), NBEAL2 (ENSG00000160796), WDFY3 (ENSG00000163625), LRBA (ENSG00000198589)

Protein

Protein identifiers

Neurobeachin — Q8NFP9 (reviewed: Q8NFP9)

Alternative names: Lysosomal-trafficking regulator 2, Protein BCL8B

All UniProt accessions (23): Q8NFP9, A0A0D9SF28, A0A8I5KQL6, A0A8I5KQP5, A0A8I5KRX1, A0A8I5KRZ1, A0A8I5KS18, A0A8I5KS58, A0A8I5KSX3, A0A8I5KTV6, A0A8I5KTY1, A0A8I5KWL1, A0A8I5KX92, A0A8I5KXL4, A0A8I5KXR7, A0A8I5KXW8, A0A8I5KXY8, A0A8I5KZ13, A0A8I5QJB2, A0A8I5QJQ0, A0A8I5QKR1, A0A8I5QKR6, Q5T321

UniProt curated annotations — full annotation on UniProt →

Function. Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the membrane. May anchor the kinase to cytoskeletal and/or organelle-associated proteins.

Subunit / interactions. Interacts with RII subunit of PKA.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Predominant in many brain structures. Also expressed at medium levels in spleen, thymus, prostate, testis and ovary. Low level expression is seen in heart, kidney, pancreas, skeletal muscle and intestine.

Disease relevance. Neurodevelopmental disorder with or without early-onset generalized epilepsy (NEDEGE) [MIM:619157] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development, speech delay, and behavioral abnormalities including autism or autistic features, attention deficits and hyperactivity, or aggressive behavior. About half of patients develop early-onset generalized epilepsy with different seizure types. The disease is apparent from infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. RII-alpha binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.

Similarity. Belongs to the WD repeat neurobeachin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NFP9-1	1	yes
Q8NFP9-2	2
Q8NFP9-3	3

RefSeq proteins (4): NP_001191126, NP_001366174, NP_001371941, NP_056493 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000409	BEACH_dom	Domain
IPR001680	WD40_rpt	Repeat
IPR010508	NBEA-like_DUF1088	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR023362	PH-BEACH_dom	Domain
IPR031570	NBEA/BDCP_DUF4704	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036372	BEACH_dom_sf	Homologous_superfamily
IPR046851	NBCH_WD40	Domain
IPR046852	Neurobeachin_a-sol	Domain
IPR050865	BEACH_Domain	Family

Pfam: PF02138, PF06469, PF13385, PF14844, PF15787, PF20425, PF20426

UniProt features (81 total): helix 22, sequence variant 14, strand 10, modified residue 7, repeat 5, region of interest 5, turn 5, compositionally biased region 4, splice variant 3, sequence conflict 3, domain 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1MI1	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

No AlphaFold model available for Q8NFP9 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (7): 1011, 1014, 1529, 1714, 1717, 2138, 2575

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-163615	PKA activation
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-111885	Opioid Signalling
R-HSA-111931	PKA-mediated phosphorylation of CREB
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1489509	DAG and IP3 signaling
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1980143	Signaling by NOTCH1
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-418594	G alpha (i) signalling events
R-HSA-442755	Activation of NMDA receptors and postsynaptic events
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): intracellular protein localization (GO:0008104), synapse organization (GO:0050808), hematopoietic stem cell homeostasis (GO:0061484), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696)

GO Molecular Function (2): protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (11): trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), endomembrane system (GO:0012505), membrane (GO:0016020), nucleus (GO:0005634), cytoplasm (GO:0005737), extrinsic component of postsynaptic membrane (GO:0098890), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), cerebellar Golgi cell to granule cell synapse (GO:0099192)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Signal Transduction	2
Transmission across Chemical Synapses	1
PKA-mediated phosphorylation of CREB	1
Signaling by NOTCH1	1
Activation of NMDA receptors and postsynaptic events	1
G alpha (i) signalling events	1
Calmodulin induced events	1
CaM pathway	1
PLC beta mediated events	1
Ca-dependent events	1
DAG and IP3 signaling	1
Opioid Signalling	1
G-protein mediated events	1
Neuronal System	1
Intracellular signaling by second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
synapse	3
macromolecule localization	1
cell junction organization	1
homeostasis of number of cells	1
regulation of biological quality	1
neurotransmitter receptor localization to postsynaptic specialization membrane	1
regulation of protein localization to synapse	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
kinase binding	1
binding	1
Golgi apparatus subcompartment	1
cytoplasm	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
postsynaptic membrane	1
extrinsic component of synaptic membrane	1

Protein interactions and networks

STRING

1178 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NBEA	MAB21L1	Q13394	898
NBEA	DCLK1	O15075	781
NBEA	PRKACA	P17612	773
NBEA	PRKACB	P22694	773
NBEA	PRKACG	P22612	772
NBEA	SMAD9	O15198	673
NBEA	DLG3	Q92796	581
NBEA	MPDZ	O75970	536
NBEA	GLRB	P48167	519
NBEA	AKAP10	O43572	490
NBEA	CNBD1	Q8NA66	484
NBEA	DST	Q03001	470
NBEA	LIN7B	Q9HAP6	469
NBEA	MAP4K1	Q92918	467
NBEA	LNX1	Q8TBB1	464
NBEA	DLG1	Q12959	464

IntAct

63 interactions, top by confidence:

A	B	Type	Score
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
FOSL2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
RBM48	NBEA	psi-mi:“MI:0914”(association)	0.530
ALOXE3	HSPA8	psi-mi:“MI:0914”(association)	0.530
STRADB	TCP1	psi-mi:“MI:0914”(association)	0.530
CTLA4	B4GALT5	psi-mi:“MI:0914”(association)	0.530
ABL1	NBEA	psi-mi:“MI:0915”(physical association)	0.400
FYN	NBEA	psi-mi:“MI:0915”(physical association)	0.400
NOTCH1	CNOT1	psi-mi:“MI:0914”(association)	0.350
MRPL21		psi-mi:“MI:0914”(association)	0.350
SHC4	CHUK	psi-mi:“MI:0914”(association)	0.350
ALOXE3	HSPD1	psi-mi:“MI:0914”(association)	0.350
RD3	GNAZ	psi-mi:“MI:0914”(association)	0.350
NAB2	GRN	psi-mi:“MI:0914”(association)	0.350
STRADB	CCT3	psi-mi:“MI:0914”(association)	0.350
ARHGAP27	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CEP135	WDR91	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
IGFBP5	RPP40	psi-mi:“MI:0914”(association)	0.350
FAM124A	MPDZ	psi-mi:“MI:0914”(association)	0.350
RGS12	WIZ	psi-mi:“MI:0914”(association)	0.350
AGAP3	HSPA8	psi-mi:“MI:0914”(association)	0.350
YJEFN3	HSPA8	psi-mi:“MI:0914”(association)	0.350
MRPL21	FDXR	psi-mi:“MI:0914”(association)	0.350
RDH8	CCT3	psi-mi:“MI:0914”(association)	0.350
RD3	LRBA	psi-mi:“MI:0914”(association)	0.350
DLG3	DLG1	psi-mi:“MI:0914”(association)	0.350

BioGRID (104): NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Proximity Label-MS), NBEA (Proximity Label-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Affinity Capture-MS), NBEA (Proximity Label-MS), NBEA (Proximity Label-MS)

ESM2 similar proteins: A0A0R4IC37, A1A4K3, A2CEI4, B1WC10, E9PY46, F1QEB7, F4IDS7, O08658, O13046, O75694, O75717, O95876, P33194, P37199, P59328, Q08D69, Q10569, Q10570, Q16531, Q32NR9, Q3U1J4, Q4ADV7, Q566H4, Q5DQR4, Q5R649, Q5U1Z0, Q5ZLG9, Q6P6Z0, Q6PGF3, Q6PJI9, Q7XWP1, Q802U2, Q805F9, Q8BMG7, Q8C0M0, Q8C456, Q8CEC0, Q8CJF7, Q8K1X1, Q8NFP9

Diamond homologs: A8XSV3, D4A929, E7FAW3, E9Q2M9, F4HZB2, F4IG73, F4JD14, F4JHT3, O35242, P0C6P0, P25356, P50851, P97412, Q19317, Q54PP7, Q54RQ8, Q55AV3, Q55DM1, Q562E7, Q5ND34, Q6VNB8, Q6ZNJ1, Q6ZQA0, Q6ZS30, Q6ZS81, Q7LKZ7, Q86JF2, Q8IZQ1, Q8NFP9, Q92636, Q99698, Q9DDD5, Q9EPN1, Q9ESE1, Q9TTK4, Q9W060, Q9W4E2, E7FEV0, F4JY12, Q10122

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NBEA	“down-regulates activity”	NOTCH1	binding
NBEA	“up-regulates activity”	DLG3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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.

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	5	28.5×	4e-04
retina development in camera-type eye	5	17.2×	2e-03
cell surface receptor protein tyrosine kinase signaling pathway	7	16.4×	2e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 11 cancer types — BRCA, CEAD, COAD, COADREAD, ESCA, HCC, LUAD, OVT, SCLC, SKCM, STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	41
Uncertain significance	588
Likely benign	175
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1206892	NM_001385012.1(NBEA):c.5649-1G>A	Pathogenic
1335130	NM_001385012.1(NBEA):c.2652-1G>C	Pathogenic
1343155	NM_001385012.1(NBEA):c.1035T>G (p.Tyr345Ter)	Pathogenic
1678665	NM_001385012.1(NBEA):c.433C>T (p.Arg145Ter)	Pathogenic
1685966	NM_001385012.1(NBEA):c.5648+1G>A	Pathogenic
1805836	NM_001385012.1(NBEA):c.3806del (p.Asp1269fs)	Pathogenic
1879251	NM_001385012.1(NBEA):c.1400C>A (p.Ser467Ter)	Pathogenic
2429963	NM_001385012.1(NBEA):c.5206dup (p.Ser1736fs)	Pathogenic
2570858	NM_001385012.1(NBEA):c.4424-1G>C	Pathogenic
2578699	NM_001385012.1(NBEA):c.639del (p.Ala213_Val214insTer)	Pathogenic
2582442	NM_001385012.1(NBEA):c.3911dup (p.Asp1304fs)	Pathogenic
2664660	NM_001385012.1(NBEA):c.3137dup (p.Ser1046fs)	Pathogenic
2671918	NM_001385012.1(NBEA):c.2657T>A (p.Leu886Ter)	Pathogenic
3063274	GRCh37/hg19 13q13.3(chr13:35778508-36035542)x1	Pathogenic
3065998	NM_001385012.1(NBEA):c.8596C>T (p.Arg2866Ter)	Pathogenic
3359080	NM_001385012.1(NBEA):c.5904-2A>G	Pathogenic
3382534	NM_001385012.1(NBEA):c.3949C>T (p.Arg1317Ter)	Pathogenic
3389720	NM_001385012.1(NBEA):c.526+1G>T	Pathogenic
3726494	NM_001385012.1(NBEA):c.1102_1111dup (p.Leu371fs)	Pathogenic
3900231	NM_001385012.1(NBEA):c.8661+1G>A	Pathogenic
4071975	NM_001385012.1(NBEA):c.6564dup (p.Phe2189fs)	Pathogenic
4531456	NM_001385012.1(NBEA):c.7491G>A (p.Trp2497Ter)	Pathogenic
4535041	NM_001385012.1(NBEA):c.972+1G>T	Pathogenic
4625797	NM_001385012.1(NBEA):c.6756_6757del (p.Tyr2252_Ser2253delinsTer)	Pathogenic
4819138	NM_001385012.1(NBEA):c.7765del (p.His2589fs)	Pathogenic
4820061	NM_001385012.1(NBEA):c.6807-2A>G	Pathogenic
4839824	NM_001385012.1(NBEA):c.2902C>T (p.Gln968Ter)	Pathogenic
973380	NM_001385012.1(NBEA):c.8659C>T (p.Arg2887Trp)	Pathogenic
976285	NM_001385012.1(NBEA):c.4662+1G>C	Pathogenic
985884	NM_001385012.1(NBEA):c.4477_4478del (p.Arg1493fs)	Pathogenic

SpliceAI

11482 predictions. Top by Δscore:

Variant	Effect	Δscore
13:34943114:GGT:G	donor_loss	1.0000
13:34943116:T:G	donor_loss	1.0000
13:34959352:G:GT	donor_gain	1.0000
13:34959404:C:CG	donor_gain	1.0000
13:35040920:T:A	acceptor_gain	1.0000
13:35040925:A:AG	acceptor_gain	1.0000
13:35040926:C:G	acceptor_gain	1.0000
13:35040928:TTCA:T	acceptor_loss	1.0000
13:35040929:TCA:T	acceptor_loss	1.0000
13:35040930:CAG:C	acceptor_loss	1.0000
13:35040931:A:AG	acceptor_gain	1.0000
13:35040931:AGCT:A	acceptor_gain	1.0000
13:35040931:AGCTG:A	acceptor_gain	1.0000
13:35040932:G:GT	acceptor_gain	1.0000
13:35040932:GC:G	acceptor_gain	1.0000
13:35040932:GCT:G	acceptor_gain	1.0000
13:35040932:GCTG:G	acceptor_gain	1.0000
13:35040932:GCTGG:G	acceptor_gain	1.0000
13:35048551:A:AG	acceptor_gain	1.0000
13:35048551:ATT:A	acceptor_gain	1.0000
13:35048552:T:G	acceptor_gain	1.0000
13:35048553:T:TA	acceptor_gain	1.0000
13:35048558:TGTA:T	acceptor_loss	1.0000
13:35048559:GTA:G	acceptor_loss	1.0000
13:35048560:TA:T	acceptor_loss	1.0000
13:35048561:A:AG	acceptor_gain	1.0000
13:35048561:AG:A	acceptor_gain	1.0000
13:35048561:AGGCA:A	acceptor_loss	1.0000
13:35048562:G:GA	acceptor_gain	1.0000
13:35048562:GG:G	acceptor_gain	1.0000

AlphaMissense

19586 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:34943113:T:C	L98P	1.000
13:35040948:T:C	F104L	1.000
13:35040950:T:A	F104L	1.000
13:35040950:T:G	F104L	1.000
13:35041009:T:C	L124P	1.000
13:35041047:T:A	W137R	1.000
13:35041047:T:C	W137R	1.000
13:35048590:T:A	W251R	1.000
13:35048590:T:C	W251R	1.000
13:35050301:C:A	A293D	1.000
13:35050382:T:C	F320S	1.000
13:35056010:T:A	W325R	1.000
13:35056010:T:C	W325R	1.000
13:35056046:T:A	W337R	1.000
13:35056046:T:C	W337R	1.000
13:35056067:T:C	C344R	1.000
13:35056074:T:A	V346D	1.000
13:35056080:G:A	G348E	1.000
13:35056080:G:T	G348V	1.000
13:35056109:T:A	W358R	1.000
13:35056109:T:C	W358R	1.000
13:35058829:T:A	I402K	1.000
13:35058835:C:A	A404E	1.000
13:35070035:T:C	L456P	1.000
13:35070764:T:C	S495P	1.000
13:35070770:G:A	G497R	1.000
13:35070770:G:C	G497R	1.000
13:35070771:G:A	G497E	1.000
13:35070771:G:T	G497V	1.000
13:35070773:G:A	G498R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000968 (13:35169102 T>C), RS1000008327 (13:35371053 C>T), RS1000012682 (13:35044130 A>G), RS1000020091 (13:35140682 A>T), RS1000024362 (13:34962154 T>C), RS1000025015 (13:35581598 T>C), RS1000025281 (13:35554265 G>T), RS1000031193 (13:35449208 T>C), RS1000031647 (13:35312581 G>A,C,T), RS1000032172 (13:35169362 C>T), RS1000039071 (13:35021859 G>A,C), RS1000042827 (13:35021109 C>A,G), RS1000053482 (13:35465722 T>A,C), RS1000054133 (13:35598375 T>A), RS1000057648 (13:35014786 G>A,T)

Disease associations

OMIM: gene MIM:604889 | disease phenotypes: MIM:619157, MIM:618479, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	Autosomal dominant
syndromic intellectual disability	Strong	Autosomal dominant
neurodevelopmental disorder with or without early-onset generalized epilepsy	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (9): neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), neurodevelopmental disorder with or without early-onset generalized epilepsy (MONDO:0030930), autism spectrum disorder (MONDO:0005258), cerebellar, ocular, craniofacial, and genital syndrome (MONDO:0032774), autism (MONDO:0005260), epilepsy (MONDO:0005027), complex neurodevelopmental disorder (MONDO:0100038), syndromic intellectual disability (MONDO:0000508)

Orphanet (2): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

22 total (23 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000964	Eczematoid dermatitis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0002136	Broad-based gait
HP:0002376	Developmental regression
HP:0002719	Recurrent infections
HP:0003593	Infantile onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0007359	Focal-onset seizure
HP:0011182	Interictal epileptiform activity
HP:0011463	Childhood onset
HP:0031936	Delayed ability to walk
HP:0032794	Myoclonic seizure
HP:0000717	Autism

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004808_1	Immunoglobulin light chain (AL) amyloidosis (serum IgG profile)	6.000000e-08
GCST004809_2	Immunoglobulin light chain (AL) amyloidosis (serum Ig lambda profile)	3.000000e-08
GCST005051_24	Obstructive sleep apnea trait (apnea hypopnea index)	6.000000e-07
GCST006292_10	Response to antipsychotic treatment in schizophrenia	9.000000e-06
GCST006680_3	Nonsyndromic cleft lip with or without cleft palate x sex interaction (2df test)	5.000000e-06
GCST008216_1	Non-muscle-invasive bladder cancer tumour size	3.000000e-09
GCST009391_246	Metabolite levels	9.000000e-06
GCST010105_184	Nicotine dependence symptom count	2.000000e-06
GCST010105_33	Nicotine dependence symptom count	2.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008366	IgG isotype profile measurement
EFO:0007817	sleep apnea measurement
EFO:0003959	cleft lip
EFO:0008343	sex interaction measurement
EFO:0008336	disease progression measurement
EFO:0010494	guanosine diphosphate measurement
EFO:0009262	nicotine dependence symptom count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs57081354	Efficacy	3	metformin	Diabetes Mellitus;Type 2
rs9315310	Efficacy	3	antidepressants	Major Depressive Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9315310	NBEA	3	0.00	1	antidepressants
rs57081354	NBEA	3	0.00	1	metformin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	5
Aflatoxin B1	affects expression, affects methylation, decreases expression	5
sodium arsenite	decreases expression, increases expression, affects methylation	3
Resveratrol	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
butyraldehyde	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Acetaminophen	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Quercetin	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	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_TA01	HAP1 NBEA (-) 1	Cancer cell line	Male
CVCL_TA02	HAP1 NBEA (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

301 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,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
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