NECAB3

Summary

NECAB3 (N-terminal EF-hand calcium binding protein 3, HGNC:15851) is a protein-coding gene on chromosome 20q11.22, encoding N-terminal EF-hand calcium-binding protein 3 (Q96P71). Inhibits the interaction of APBA2 with amyloid-beta precursor protein (APP), and hence allows formation of amyloid-beta.

The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 63941 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 72 total
• MANE Select transcript: NM_031232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15851
Approved symbol	NECAB3
Name	N-terminal EF-hand calcium binding protein 3
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	XB51, dJ63M2.4, NIP1, dJ63M2.5, EFCBP3
Ensembl gene	ENSG00000125967
Ensembl biotype	protein_coding
OMIM	612478
Entrez	63941

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 9 protein_coding, 9 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000246190, ENST00000375238, ENST00000439478, ENST00000463246, ENST00000473892, ENST00000477778, ENST00000478237, ENST00000480994, ENST00000483813, ENST00000484824, ENST00000485399, ENST00000485976, ENST00000488489, ENST00000493590, ENST00000494174, ENST00000498353, ENST00000606106, ENST00000606525, ENST00000606690, ENST00000606699, ENST00000607055, ENST00000607805, ENST00000883745, ENST00000883746, ENST00000883747

RefSeq mRNA: 2 — MANE Select: NM_031232 NM_031231, NM_031232

CCDS: CCDS42866, CCDS42867

Canonical transcript exons

ENST00000246190 — 12 exons

Exon	Start	End
ENSE00001841294	33657087	33657857
ENSE00003527081	33657942	33658033
ENSE00003582292	33659885	33660003
ENSE00003652847	33659497	33659732
ENSE00003695705	33660259	33660395
ENSE00003696139	33669375	33669472
ENSE00003699913	33672398	33672422
ENSE00003699944	33670684	33670792
ENSE00003699987	33658477	33658554
ENSE00003700828	33669687	33669712
ENSE00003701368	33658722	33658834
ENSE00003903202	33674224	33674428

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 97.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6238 / max 117.2940, expressed in 1791 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186968	18.6857	1783
186966	1.3548	810
186965	0.4887	265
186967	0.0578	21
186964	0.0334	10
186963	0.0033	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	97.16	gold quality
right adrenal gland	UBERON:0001233	96.96	gold quality
left adrenal gland	UBERON:0001234	96.55	gold quality
left adrenal gland cortex	UBERON:0035825	96.55	gold quality
left ovary	UBERON:0002119	96.52	gold quality
right ovary	UBERON:0002118	96.15	gold quality
adrenal cortex	UBERON:0001235	95.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.68	gold quality
apex of heart	UBERON:0002098	95.34	gold quality
adrenal gland	UBERON:0002369	95.14	gold quality
mucosa of stomach	UBERON:0001199	94.36	gold quality
gastrocnemius	UBERON:0001388	94.01	gold quality
body of stomach	UBERON:0001161	93.73	gold quality
muscle of leg	UBERON:0001383	93.71	gold quality
right lobe of thyroid gland	UBERON:0001119	93.44	gold quality
right testis	UBERON:0004534	93.41	gold quality
heart left ventricle	UBERON:0002084	93.16	gold quality
right atrium auricular region	UBERON:0006631	93.13	gold quality
right frontal lobe	UBERON:0002810	93.06	gold quality
left testis	UBERON:0004533	93.06	gold quality
cardiac ventricle	UBERON:0002082	92.84	gold quality
prefrontal cortex	UBERON:0000451	92.76	gold quality
left lobe of thyroid gland	UBERON:0001120	92.51	gold quality
ovary	UBERON:0000992	92.34	gold quality
muscle organ	UBERON:0001630	92.12	gold quality
adrenal tissue	UBERON:0018303	92.04	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.83	gold quality
cardiac atrium	UBERON:0002081	91.82	gold quality
primary visual cortex	UBERON:0002436	91.76	gold quality
stomach	UBERON:0000945	91.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting NECAB3, 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-4692	100.00	67.32	2066
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-5001-5P	99.05	66.76	1972

Literature-anchored findings (GeneRIF, showing 4)

• hXB51 isoforms regulate Abeta generation differently, either enhancing it by modifying the association of X11L with APP or suppressing it in an X11L-independent manner (PMID:12780348)
• xb51 may be required for maturation and maintenance of xb51-expressing neurons in the forebrain (PMID:19035353)
• Results suggest that NECAB3, a novel Mint3-binding protein, activates HIF-1 to promote normoxic glycolysis and tumorigenicity by forming a ternary complex with Mint3 and FIH-1. (PMID:26948053)
• GNAS-AS1/miR-4319/NECAB3 axis promotes tumor progression of non-small cell lung cancer by altering macrophage polarization. (PMID:31267263)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	necab3	ENSDARG00000074794
mus_musculus	Necab3	ENSMUSG00000027489
rattus_norvegicus	E2f1	ENSRNOG00000016708

Paralogs (2): NECAB2 (ENSG00000103154), NECAB1 (ENSG00000123119)

Protein

Protein identifiers

N-terminal EF-hand calcium-binding protein 3 — Q96P71 (reviewed: Q96P71)

Alternative names: Amyloid-beta A4 protein-binding family A member 2-binding protein, Nek2-interacting protein 1, Neuronal calcium-binding protein 3, X11L-binding protein 51

All UniProt accessions (9): Q96P71, U3KPZ3, U3KQ06, U3KQC6, U3KQF5, U3KQJ7, U3KQM7, U3KQR6, X6RCW6

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits the interaction of APBA2 with amyloid-beta precursor protein (APP), and hence allows formation of amyloid-beta. May enhance the activity of HIF1A and thus promote glycolysis under normoxic conditions; the function requires its ABM domain and may implicate the stabilization of the interaction between HIF1AN and APBA3.

Subunit / interactions. Interacts with the N-terminal domain of APBA2. Interacts with NEK2. Interacts with APBA3; APBA3 seems to mediate the interaction between NECAB3 and HIF1AN.

Subcellular location. Golgi apparatus.

Tissue specificity. Strongly expressed in heart and skeletal muscle, moderately in brain and pancreas.

Post-translational modifications. Phosphorylated by NEK2.

Miscellaneous. May result from the retention of an intron in the cDNA.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96P71-1	2, XB51-alpha	yes
Q96P71-2	1, XB51-beta
Q96P71-3	3

RefSeq proteins (2): NP_112508, NP_112509* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR007138	ABM_dom	Domain
IPR011008	Dimeric_a/b-barrel	Homologous_superfamily
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR039862	NECAB1/2/3	Family

Pfam: PF03992, PF13202

UniProt features (19 total): binding site 5, splice variant 3, region of interest 3, domain 2, compositionally biased region 2, chain 1, sequence variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96P71-F1	71.76	0.35

Functional residue map

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

Ligand- & substrate-binding residues (5): 53; 55; 60; 49; 51

Mutagenesis-validated functional residues (1):

Position	Phenotype
358	no effect on interaction with apba3.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 122 (showing top): AP1_01, PAX4_01, CHANDRAN_METASTASIS_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, MODULE_66, PAX8_B, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, HFH8_01, GOBP_SECRETION, TGANTCA_AP1_C, NRF2_Q4, MODULE_88, TGGNNNNNNKCCAR_UNKNOWN, GOBP_AMYLOID_PRECURSOR_PROTEIN_METABOLIC_PROCESS

GO Biological Process (3): protein secretion (GO:0009306), protein metabolic process (GO:0019538), regulation of amyloid precursor protein biosynthetic process (GO:0042984)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): Golgi cis cisterna (GO:0000137), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cytoplasm	2
endomembrane system	2
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
macromolecule metabolic process	1
primary metabolic process	1
regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
metal ion binding	1
binding	1
cation binding	1
Golgi cisterna	1
intracellular anatomical structure	1
cellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1107 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NECAB3	APBA2	Q99767	880
NECAB3	NEK2	P51955	735
NECAB3	ACTL10	Q5JWF8	620
NECAB3	MFSD6L	Q8IWD5	521
NECAB3	APP	P05067	499
NECAB3	ARMCX4	Q5H9R4	498
NECAB3	C20orf144	Q9BQM9	479
NECAB3	ZMYM6	O95789	478
NECAB3	CACHD1	Q5VU97	474
NECAB3	AP4S1	Q9Y587	458
NECAB3	UBAC2	Q8NBM4	449
NECAB3	CACNB3	P54284	443
NECAB3	TAX1BP3	O14907	437
NECAB3	S100A5	P33763	433
NECAB3	RAB30	Q15771	433

IntAct

13 interactions, top by confidence:

A	B	Type	Score
HIF1AN	APBA3	psi-mi:“MI:0915”(physical association)	0.850
APBA3	NECAB3	psi-mi:“MI:0915”(physical association)	0.630
APBA3	DUSP11	psi-mi:“MI:0914”(association)	0.530
NECAB1	CCDC6	psi-mi:“MI:0914”(association)	0.530
APBA3	CLSTN1	psi-mi:“MI:0914”(association)	0.530
NECAB3	FXR1	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
NECAB2	PCM1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	NECAB3	psi-mi:“MI:0915”(physical association)	0.000
NECAB3	IKBKG	psi-mi:“MI:0407”(direct interaction)	0.000

BioGRID (16): NECAB3 (Affinity Capture-MS), NECAB3 (Affinity Capture-MS), NECAB3 (Affinity Capture-MS), NECAB3 (Affinity Capture-MS), NECAB3 (Affinity Capture-RNA), NECAB3 (Affinity Capture-Western), NECAB3 (Two-hybrid), NECAB3 (Affinity Capture-MS), NECAB3 (Affinity Capture-MS), NECAB3 (Affinity Capture-MS), NECAB3 (Two-hybrid), NECAB3 (Two-hybrid), NECAB3 (Affinity Capture-RNA), NECAB3 (Reconstituted Complex), NECAB3 (Dosage Lethality)

ESM2 similar proteins: A1L515, A4D2P6, A6QQD2, A8VU90, E1BDF2, O75808, O88995, P0CG25, P22083, Q0IIA6, Q2TA57, Q3B7L1, Q3MIP1, Q3U5Q7, Q3UR50, Q3UR97, Q3UV16, Q400G9, Q5BKX5, Q5EBM0, Q5GH72, Q5SZI1, Q5TM19, Q5U4P2, Q62994, Q659K9, Q6PRD1, Q7Z736, Q861W0, Q86UR1, Q8BNN1, Q8C0R7, Q8CG70, Q8IUW3, Q8IVL6, Q8N398, Q8NAG6, Q8NCW0, Q8R2H1, Q8VCE9

Diamond homologs: A2VDW6, F1LQY6, Q5R467, Q7Z6G3, Q8BG18, Q8N987, Q91ZP9, Q96P71, Q9D6J4, Q9ESB5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3256 predictions. Top by Δscore:

Variant	Effect	Δscore
20:33658034:C:CC	acceptor_gain	1.0000
20:33658551:CACA:C	acceptor_gain	1.0000
20:33658553:CA:C	acceptor_gain	1.0000
20:33658555:C:CC	acceptor_gain	1.0000
20:33658720:A:AC	donor_gain	1.0000
20:33658721:C:CT	donor_gain	1.0000
20:33658721:CTG:C	donor_gain	1.0000
20:33658830:ATGTG:A	acceptor_gain	1.0000
20:33658832:GTG:G	acceptor_gain	1.0000
20:33658833:TG:T	acceptor_gain	1.0000
20:33658833:TGCT:T	acceptor_loss	1.0000
20:33658834:GCT:G	acceptor_loss	1.0000
20:33658835:C:CC	acceptor_gain	1.0000
20:33658835:C:CG	acceptor_loss	1.0000
20:33659647:CCTCA:C	donor_loss	1.0000
20:33659649:TCACC:T	donor_loss	1.0000
20:33659650:CACCT:C	donor_loss	1.0000
20:33659651:A:AG	donor_loss	1.0000
20:33660254:CATA:C	donor_gain	1.0000
20:33660255:ATACC:A	donor_loss	1.0000
20:33660256:TAC:T	donor_loss	1.0000
20:33660257:A:AC	donor_gain	1.0000
20:33660257:ACCG:A	donor_gain	1.0000
20:33660258:C:CC	donor_gain	1.0000
20:33660258:C:CG	donor_loss	1.0000
20:33660258:CCG:C	donor_gain	1.0000
20:33660258:CCGC:C	donor_gain	1.0000
20:33660391:TACTC:T	acceptor_gain	1.0000
20:33660393:CTC:C	acceptor_gain	1.0000
20:33660394:TC:T	acceptor_gain	1.0000

AlphaMissense

2562 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:33660363:A:C	F140L	0.998
20:33660363:A:T	F140L	0.998
20:33660365:A:G	F140L	0.998
20:33660351:G:C	F144L	0.996
20:33660351:G:T	F144L	0.996
20:33660352:A:G	F144S	0.996
20:33660353:A:G	F144L	0.996
20:33660364:A:G	F140S	0.994
20:33660346:A:G	L146P	0.993
20:33660349:A:G	L145P	0.993
20:33660364:A:C	F140C	0.992
20:33660325:A:G	L153P	0.991
20:33670764:G:C	F61L	0.990
20:33670764:G:T	F61L	0.990
20:33670765:A:G	F61S	0.990
20:33670766:A:G	F61L	0.990
20:33669466:A:G	F99S	0.984
20:33658500:C:A	W349C	0.982
20:33658500:C:G	W349C	0.982
20:33660316:A:G	L156P	0.982
20:33660340:T:A	E148V	0.982
20:33660352:A:C	F144C	0.982
20:33660355:C:G	R143P	0.982
20:33669415:A:G	L116P	0.982
20:33670752:A:C	F65L	0.982
20:33670752:A:T	F65L	0.982
20:33670754:A:G	F65L	0.982
20:33660343:C:G	R147P	0.981
20:33658502:A:G	W349R	0.980
20:33658502:A:T	W349R	0.980

dbSNP variants (sampled 300 via entrez): RS1000188291 (20:33673307 T>A), RS1000197218 (20:33660914 C>G), RS1000223854 (20:33670716 T>C), RS1000243510 (20:33671998 C>A,G,T), RS1000357529 (20:33667458 G>A,T), RS1000451973 (20:33673687 G>T), RS1000765217 (20:33665958 C>T), RS1000858679 (20:33670433 G>A), RS1000962550 (20:33676496 C>T), RS1001002474 (20:33677017 C>T), RS1001192392 (20:33674466 G>GCCCCGC), RS1001427673 (20:33668303 T>C,G), RS1001454227 (20:33674670 A>G), RS1001514865 (20:33673371 A>C), RS1001928592 (20:33662021 G>C)

Disease associations

OMIM: gene MIM:612478 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, increases abundance	3
Arsenic	affects methylation, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, increases expression	1
Fulvestrant	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Gold Compounds	increases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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