NFAM1

Summary

NFAM1 (NFAT activating protein with ITAM motif 1, HGNC:29872) is a protein-coding gene on chromosome 22q13.2, encoding NFAT activation molecule 1 (Q8NET5). May function in immune system as a receptor which activates via the calcineurin/NFAT-signaling pathway the downstream cytokine gene promoters.

The protein encoded by this gene is a type I membrane receptor that activates cytokine gene promoters such as the IL-13 and TNF-alpha promoters. The encoded protein contains an immunoreceptor tyrosine-based activation motif (ITAM) and is thought to regulate the signaling and development of B-cells.

Source: NCBI Gene 150372 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 63 total
• MANE Select transcript: NM_145912

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29872
Approved symbol	NFAM1
Name	NFAT activating protein with ITAM motif 1
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	CNAIP
Ensembl gene	ENSG00000235568
Ensembl biotype	protein_coding
OMIM	608740
Entrez	150372

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000329021, ENST00000355469, ENST00000968877

RefSeq mRNA: 3 — MANE Select: NM_145912 NM_001318323, NM_001371362, NM_145912

CCDS: CCDS14034

Canonical transcript exons

ENST00000329021 — 6 exons

Exon	Start	End
ENSE00001620427	42411407	42411736
ENSE00001674692	42409435	42409547
ENSE00001722461	42397858	42397956
ENSE00001736442	42432237	42432403
ENSE00001762075	42386989	42387078
ENSE00001802295	42380407	42385220

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 96.50.

FANTOM5 (CAGE): breadth broad, TPM avg 14.1896 / max 1056.1684, expressed in 453 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194429	7.7879	440
194428	6.4017	337

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.50	gold quality
leukocyte	CL:0000738	96.42	gold quality
blood	UBERON:0000178	95.13	gold quality
granulocyte	CL:0000094	94.40	gold quality
upper arm skin	UBERON:0004263	90.32	silver quality
pancreatic ductal cell	CL:0002079	89.40	gold quality
bone marrow cell	CL:0002092	86.79	gold quality
tendon of biceps brachii	UBERON:0008188	86.71	silver quality
kidney epithelium	UBERON:0004819	86.69	silver quality
left ventricle myocardium	UBERON:0006566	85.27	gold quality
bone marrow	UBERON:0002371	84.90	gold quality
cardiac muscle of right atrium	UBERON:0003379	84.43	gold quality
epithelial cell of pancreas	CL:0000083	84.05	silver quality
spleen	UBERON:0002106	83.26	gold quality
buccal mucosa cell	CL:0002336	82.62	silver quality
vermiform appendix	UBERON:0001154	82.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.03	gold quality
trabecular bone tissue	UBERON:0002483	81.78	gold quality
caecum	UBERON:0001153	80.89	gold quality
myocardium	UBERON:0002349	80.87	gold quality
cerebellar vermis	UBERON:0004720	80.31	silver quality
layer of synovial tissue	UBERON:0007616	79.08	gold quality
sperm	CL:0000019	78.88	silver quality
deltoid	UBERON:0001476	78.64	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.30	gold quality
tibialis anterior	UBERON:0001385	77.70	silver quality
ileal mucosa	UBERON:0000331	77.62	gold quality
vena cava	UBERON:0004087	77.56	gold quality
nipple	UBERON:0002030	77.08	gold quality
cartilage tissue	UBERON:0002418	77.06	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	23.26
E-ANND-3	yes	11.17
E-MTAB-9801	yes	6.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CD40LG
CSF2
IL2
IL4
IL5

miRNA regulators (miRDB)

182 targeting NFAM1, 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-5193	100.00	67.26	1744
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-1273H-5P	99.77	66.32	2471

Literature-anchored findings (GeneRIF, showing 7)

• CNAIP is a ITAM-containing protein that activates the calcineurin/NFAT-signaling pathway and the downstream cytokine gene promoters (PMID:12615919)
• Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature. (PMID:17079331)
• NFAT plays a role in SV40 infection via transcriptional control of Simian Virus 40. (PMID:18031784)
• Our findings define a pathway involving CD28 binding to Grb-2 and its co-operativity with Vav1 in the regulation of T-cell co-stimulation. (PMID:18295596)
• NFAT activating protein with ITAM motif 1 (NFAM1) is upregulated on circulating monocytes in coronary artery disease and potentially correlated with monocyte chemotaxis. (PMID:32711213)
• NFAM1 Promotes Pro-Inflammatory Cytokine Production in Mouse and Human Monocytes. (PMID:35095847)
• Extracellular Vesicle-Derived circITGB1 Regulates Dendritic Cell Maturation and Cardiac Inflammation via miR-342-3p/NFAM1. (PMID:35615580)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nfam1	ENSMUSG00000058099
rattus_norvegicus	Nfam1	ENSRNOG00000022975

Protein

Protein identifiers

NFAT activation molecule 1 — Q8NET5 (reviewed: Q8NET5)

Alternative names: Calcineurin/NFAT-activating ITAM-containing protein, NFAT-activating protein with ITAM motif 1

All UniProt accessions (1): Q8NET5

UniProt curated annotations — full annotation on UniProt →

Function. May function in immune system as a receptor which activates via the calcineurin/NFAT-signaling pathway the downstream cytokine gene promoters. Activates the transcription of IL-13 and TNF promoters. May be involved in the regulation of B-cell, but not T-cell, development. Overexpression activates downstream effectors without ligand binding or antibody cross-linking.

Subunit / interactions. No direct interaction with the B-cell antigen receptor (BCR). Interacts with SYK; probably involved in BCR signaling. Interacts with ZAP70.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in neutrophils, primary monocytes, mast cells, monocytic cell lines and lymphocytes. Also expressed in spleen B and T-cells, and lung. Expressed at low level in non-immune tissue.

Post-translational modifications. N-glycosylated.

Domain organisation. The ITAM domain displays no close similarity to any existing ITAMs, except for four conserved positions. The phosphorylated ITAM domain binds ZAP70 and SYK.

RefSeq proteins (3): NP_001305252, NP_001358291, NP_666017* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003110	Phos_immunorcpt_sig_ITAM	Repeat
IPR033549	NFAM1	Family
IPR057883	Ig_NFAM1	Domain

Pfam: PF25830

UniProt features (20 total): compositionally biased region 3, modified residue 2, sequence variant 2, mutagenesis site 2, topological domain 2, domain 2, region of interest 2, signal peptide 1, chain 1, glycosylation site 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NET5-F1	72.19	0.44

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 (2): 220, 231

Disulfide bonds (1): 65–114

Glycosylation sites (1): 107

Mutagenesis-validated functional residues (2):

Position	Phenotype
220	abolishes the itam-mediated-activating activity.
231	abolishes the itam-mediated-activating activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 186 (showing top): GOBP_REGULATION_OF_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_B_CELL_DIFFERENTIATION

GO Biological Process (10): positive regulation of cytokine production (GO:0001819), inflammatory response (GO:0006954), signal transduction (GO:0007165), B cell differentiation (GO:0030183), calcineurin-NFAT signaling cascade (GO:0033173), intracellular signal transduction (GO:0035556), regulation of B cell differentiation (GO:0045577), B cell receptor signaling pathway (GO:0050853), positive regulation of B cell receptor signaling pathway (GO:0050861), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (2): transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), membrane (GO:0016020), azurophil granule membrane (GO:0035577), membrane raft (GO:0045121)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lymphocyte differentiation	1
B cell activation	1
calcineurin-mediated signaling	1
intracellular anatomical structure	1
B cell differentiation	1
regulation of lymphocyte differentiation	1
regulation of B cell activation	1
antigen receptor-mediated signaling pathway	1
B cell receptor signaling pathway	1
regulation of B cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1
membrane microdomain	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFAM1	SYK	P43405	592
NFAM1	ZAP70	P43403	551
NFAM1	IL13	P35225	449
NFAM1	KRT37	O76014	385
NFAM1	KDM8	Q8N371	385
NFAM1	TARBP1	Q13395	369
NFAM1	CD8A	P01732	355
NFAM1	HACD3	Q9P035	327
NFAM1	GFM1	Q96RP9	318
NFAM1	MYSM1	Q5VVJ2	315
NFAM1	SDR16C5	Q8N3Y7	306
NFAM1	TMEM129	A0AVI4	298
NFAM1	CCDC47	Q96A33	297
NFAM1	ZNF18	P17022	293
NFAM1	CCDC9	Q9Y3X0	291

IntAct

13 interactions, top by confidence:

A	B	Type	Score
NFAM1	HSPA14	psi-mi:“MI:0915”(physical association)	0.590
MAL2	NFAM1	psi-mi:“MI:0915”(physical association)	0.560
NFAM1	BCL11A	psi-mi:“MI:0915”(physical association)	0.560
TCF4	NFAM1	psi-mi:“MI:0915”(physical association)	0.560
NFAM1	MAL2	psi-mi:“MI:0915”(physical association)	0.560
NFAM1	A2ML1	psi-mi:“MI:0914”(association)	0.350
NFAM1	BCL11A	psi-mi:“MI:0915”(physical association)	0.000
NFAM1	TCF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): HSPA14 (Affinity Capture-MS), HSPA14 (Affinity Capture-MS), NFAM1 (Two-hybrid), NFAM1 (Two-hybrid), NFAM1 (Two-hybrid), HSPA14 (Affinity Capture-MS), APOD (Affinity Capture-MS), SDR9C7 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), A2ML1 (Affinity Capture-MS), LCN2 (Affinity Capture-MS), SERPINA3 (Affinity Capture-MS), NFAM1 (PCA), NFAM1 (Co-localization)

ESM2 similar proteins: A0A1B0GU29, A6NLX4, A6QNY1, A9CBA0, B7ZWI3, O14669, O88472, P14784, P16297, P25918, P26896, Q0VFL4, Q13651, Q32M26, Q38J84, Q38J85, Q3SYS8, Q58CT8, Q5BK39, Q5EAA5, Q5HZE8, Q5NCP0, Q5RCL0, Q64322, Q68DV7, Q6AXS2, Q6AXU5, Q6NUJ2, Q6UWV7, Q86UW2, Q8BHB3, Q8BLR5, Q8BSU2, Q8C353, Q8C708, Q8K1T1, Q8MII8, Q8N6P7, Q8NET5, Q8R182

Diamond homologs: Q8NET5, Q8R4V1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	9
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1048 predictions. Top by Δscore:

Variant	Effect	Δscore
22:42387079:C:CC	acceptor_gain	1.0000
22:42387080:T:G	acceptor_loss	1.0000
22:42397856:A:AC	donor_gain	1.0000
22:42397857:C:CC	donor_gain	1.0000
22:42409548:C:CC	acceptor_gain	1.0000
22:42411734:CTC:C	acceptor_gain	1.0000
22:42411736:CCTGG:C	acceptor_loss	1.0000
22:42411737:C:CC	acceptor_gain	1.0000
22:42411738:T:A	acceptor_loss	1.0000
22:42385074:A:AC	donor_gain	0.9900
22:42385074:ACT:A	donor_gain	0.9900
22:42385075:C:CC	donor_gain	0.9900
22:42385075:CTC:C	donor_gain	0.9900
22:42385077:C:CA	donor_gain	0.9900
22:42385077:CCCA:C	donor_gain	0.9900
22:42386984:TGTAC:T	donor_loss	0.9900
22:42386985:GTACC:G	donor_loss	0.9900
22:42386986:TAC:T	donor_loss	0.9900
22:42386987:ACC:A	donor_loss	0.9900
22:42387075:GAGC:G	acceptor_gain	0.9900
22:42387076:AGC:A	acceptor_gain	0.9900
22:42387077:GC:G	acceptor_gain	0.9900
22:42387078:CC:C	acceptor_gain	0.9900
22:42397954:CTT:C	acceptor_gain	0.9900
22:42397956:TC:T	acceptor_loss	0.9900
22:42397957:C:CC	acceptor_gain	0.9900
22:42397957:CTGT:C	acceptor_loss	0.9900
22:42397958:T:G	acceptor_loss	0.9900
22:42409429:CCGTA:C	donor_loss	0.9900
22:42409430:CGTAC:C	donor_loss	0.9900

AlphaMissense

1725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:42409468:A:C	S177R	0.992
22:42409468:A:T	S177R	0.992
22:42409470:T:G	S177R	0.992
22:42411420:G:C	F146L	0.989
22:42411420:G:T	F146L	0.989
22:42411422:A:G	F146L	0.989
22:42411473:A:C	Y129D	0.984
22:42411453:C:A	W135C	0.982
22:42411453:C:G	W135C	0.982
22:42411664:C:G	C65S	0.979
22:42411665:A:T	C65S	0.979
22:42411664:C:T	C65Y	0.978
22:42411665:A:G	C65R	0.978
22:42409477:A:C	S174R	0.977
22:42409477:A:T	S174R	0.977
22:42409479:T:G	S174R	0.977
22:42411466:C:G	C131S	0.977
22:42411467:A:T	C131S	0.977
22:42411418:A:G	I147T	0.975
22:42411466:C:T	C131Y	0.974
22:42411479:C:A	G127C	0.974
22:42411465:G:C	C131W	0.973
22:42411467:A:G	C131R	0.973
22:42411478:C:A	G127V	0.970
22:42411663:G:C	C65W	0.970
22:42385171:T:A	E268V	0.969
22:42411418:A:T	I147N	0.967
22:42411421:A:C	F146C	0.966
22:42411418:A:C	I147S	0.961
22:42411518:A:G	C114R	0.961

dbSNP variants (sampled 300 via entrez): RS1000021472 (22:42384661 G>A,T), RS1000023655 (22:42419688 C>T), RS1000079611 (22:42420748 T>C), RS1000136229 (22:42385483 T>A), RS1000168358 (22:42408431 G>A), RS1000200354 (22:42414988 A>G), RS1000324611 (22:42405543 G>A,T), RS1000398035 (22:42405357 G>A,C), RS1000417526 (22:42438602 G>C,T), RS1000437716 (22:42404809 G>A), RS1000469977 (22:42438967 T>A,C), RS1000483973 (22:42436066 C>T), RS1000486130 (22:42414734 G>A), RS1000499325 (22:42399478 AAGAG>A,AAG,AAGAGAG,AAGAGAGAG), RS1000555878 (22:42420598 T>C)

Disease associations

OMIM: gene MIM:608740 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007323_38	Risk-taking tendency (4-domain principal component model)	2.000000e-08
GCST007576_440	Chronotype	8.000000e-12
GCST010002_83	Refractive error	2.000000e-27
GCST010248_8	Machado-Joseph disease (age at onset)	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
Triclosan	increases methylation, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
terbufos	increases methylation	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
abrine	increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
Atrazine	increases expression	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methapyrilene	affects methylation	1
Parathion	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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