FYB1

Summary

FYB1 (FYN binding protein 1, HGNC:4036) is a protein-coding gene on chromosome 5p13.1, encoding FYN-binding protein 1 (O15117). Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells.

The protein encoded by this gene is an adapter for the FYN protein and LCP2 signaling cascades in T-cells. The encoded protein is involved in platelet activation and controls the expression of interleukin-2. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2533 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombocytopenia 3 (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 236 total — 2 pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_001465

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4036
Approved symbol	FYB1
Name	FYN binding protein 1
Location	5p13.1
Locus type	gene with protein product
Status	Approved
Aliases	SLAP-130, FYB-120/130, ADAP
Ensembl gene	ENSG00000082074
Ensembl biotype	protein_coding
OMIM	602731
Entrez	2533

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000351578, ENST00000503065, ENST00000504542, ENST00000506557, ENST00000509072, ENST00000510188, ENST00000512138, ENST00000512982, ENST00000515010, ENST00000642942, ENST00000644817, ENST00000646045, ENST00000646444, ENST00000647313, ENST00000909807, ENST00000909808, ENST00000909809

RefSeq mRNA: 5 — MANE Select: NM_001465 NM_001243093, NM_001349333, NM_001465, NM_018594, NM_199335

CCDS: CCDS47200, CCDS54848, CCDS58945

Canonical transcript exons

ENST00000512982 — 19 exons

Exon	Start	End
ENSE00000741865	39134208	39134349
ENSE00000802107	39127741	39127807
ENSE00000802112	39153448	39153604
ENSE00000971278	39134855	39135014
ENSE00000971282	39119535	39119634
ENSE00000971283	39118874	39119036
ENSE00001008625	39130590	39130612
ENSE00001008629	39138657	39138691
ENSE00001008632	39137600	39137720
ENSE00001008634	39124253	39124278
ENSE00001083665	39125998	39126135
ENSE00001285024	39141095	39141141
ENSE00001285036	39122336	39122402
ENSE00001285088	39110356	39110389
ENSE00001378592	39108231	39108262
ENSE00001641713	39139233	39139252
ENSE00002042655	39219443	39219563
ENSE00003581999	39201826	39202987
ENSE00003842361	39105252	39107465

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 99.27.

FANTOM5 (CAGE): breadth broad, TPM avg 40.4995 / max 4128.0734, expressed in 665 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61389	22.7333	552
61384	6.8427	207
61392	5.2160	411
61385	3.0394	232
61390	1.1639	257
61394	0.4783	151
61393	0.3695	110
61383	0.3179	129
61395	0.2506	104
61396	0.0644	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.27	gold quality
mononuclear cell	CL:0000842	99.13	gold quality
leukocyte	CL:0000738	98.97	gold quality
blood	UBERON:0000178	97.71	gold quality
lymph node	UBERON:0000029	96.02	gold quality
bone marrow cell	CL:0002092	95.65	gold quality
bone marrow	UBERON:0002371	95.24	gold quality
trabecular bone tissue	UBERON:0002483	95.21	gold quality
vermiform appendix	UBERON:0001154	95.07	gold quality
granulocyte	CL:0000094	94.91	gold quality
spleen	UBERON:0002106	92.31	gold quality
type B pancreatic cell	CL:0000169	91.74	gold quality
colonic epithelium	UBERON:0000397	91.73	gold quality
caecum	UBERON:0001153	91.21	gold quality
epithelium of nasopharynx	UBERON:0001951	91.01	gold quality
tonsil	UBERON:0002372	90.97	gold quality
thymus	UBERON:0002370	89.87	gold quality
olfactory bulb	UBERON:0002264	89.71	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.19	gold quality
gall bladder	UBERON:0002110	88.16	gold quality
periodontal ligament	UBERON:0008266	87.60	gold quality
visceral pleura	UBERON:0002401	85.89	gold quality
palpebral conjunctiva	UBERON:0001812	85.83	gold quality
superficial temporal artery	UBERON:0001614	85.77	gold quality
rectum	UBERON:0001052	85.73	gold quality
diaphragm	UBERON:0001103	85.28	gold quality
right lung	UBERON:0002167	84.94	gold quality
parietal pleura	UBERON:0002400	84.80	gold quality
pleura	UBERON:0000977	84.23	gold quality
smooth muscle tissue	UBERON:0001135	83.86	gold quality

Single-cell (SCXA)

Detected in 33 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	1652.29
E-CURD-122	yes	1564.53
E-CURD-46	yes	1007.30
E-MTAB-8530	yes	912.86
E-HCAD-1	yes	795.29
E-GEOD-130473	yes	247.81
E-MTAB-3929	yes	173.67
E-HCAD-4	yes	109.92
E-MTAB-8142	yes	81.76
E-HCAD-8	yes	57.19
E-HCAD-35	yes	46.64
E-GEOD-84465	yes	38.87
E-MTAB-8410	yes	37.59
E-MTAB-10287	yes	37.53
E-MTAB-6678	yes	36.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2

miRNA regulators (miRDB)

121 targeting FYB1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4778-3P	99.93	70.40	1818

Literature-anchored findings (GeneRIF, showing 27)

• ADAP lipid interaction defines the helically extended SH3 scaffold as a novel member of membrane interaction domains (PMID:15843031)
• show in an ADAP-deficient Jurkat T cell line that the co-dependence of ADAP and SKAP55 extends beyond their functional and physical interactions and show that SKAP55 protein is unstable in the absence of ADAP (PMID:15849195)
• Lipid binding of ADAP at the immunological synapse most likely contributes to the function of ADAP as a regulator of T cell migration and adhesion. (PMID:16831444)
• An eight-membered ring formed upon oxidation of two neighboring cysteines leads to significant changes in the variable arginine-threonine (RT) loop of the hSH3N domain of this protein. (PMID:17511475)
• ADAP-deficient T-cell-receptor transgenic T cells demonstrate that ADAP is a positive regulator of antigen-dependent, LFA-1 integrin-mediated T cell conjugate formation with antigen presenting cells. (PMID:17785790)
• Naive transgenic ADAP-deficient T cells show impaired adhesion to ovalbumin fragment-bearing antigen-presenting cells that is restored following reconstitution with wild-type ADAP. (PMID:18802088)
• Mass spectrometric identification of ADAP associated with EVL, an actin-binding protein of the ENA/VASP family, DOCK2 and GEF-H1 suggests a direct link between ADAP and the cytoskeleton. (PMID:19798671)
• the ADAP CARMA1 binding site is required for IKK gamma ubiquitination; both TAK1 and CARMA1 binding sites are required for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation (PMID:20164171)
• a functional cooperation between Nck and ADAP in stabilizing the recruitment of WASp to SLP76 regulates actin rearrangement. (PMID:21536650)
• TM4SF10, possibly through ADAP, may regulate Fyn activity (PMID:21881001)
• our findings indicate an association between polymorphisms located in FYB gene and SLE, suggesting their possible involvement in disease susceptibility and clinical manifestations. (PMID:23628395)
• Multipoint binding of SLP-76 to ADAP facilitates the assembly of SLP-76 microclusters. (PMID:23979596)
• These findings indicate that ADAP regulates two steps of HIV-1 infection cooperatively with two distinct receptors, and as such, serves as a new potential target in the blockade of HIV-1 infection. (PMID:24047317)
• ADAP interacts with talin and kindlin-3 to promote platelet Integrin alphaIIbbeta3 activation and stable fibrinogen binding. (PMID:24523237)
• ADAP and Nck adapter proteins cooperatively facilitate T cell adhesion to the LFA-1 ligand ICAM-1. (PMID:24769494)
• The autosomal recessive bleeding phenotype seen in several members of this highly consanguineous family included petechial rash, mild epistaxis and thrombocytopenia with some decrease in platelet volume. These clinical findings, together with the results of exome sequencing pointed to only one strong candidate gene, the FYB gene. (PMID:25516138)
• The aim of this study was to perform an association study between seven Fyn-binding protein gene (FYB)-tag single nucleotide polymorphisms (SNPs) and type I diabetes mellitus (T1DM), as well as with disease age of onset. (PMID:25729932)
• FYB nonsense mutations in humans causing small-platelet thrombocytopenia and a significant bleeding tendency. (PMID:25876182)
• Data (including data from studies in knockout/transgenic mice) suggest that ADAP regulates positive feedback loop of TGFbeta1 production and TGFbeta1-induced CD103 expression in CD8+ T-lymphocytes and protects against influenza H5N1 virus infection. (PMID:25909459)
• Data strongly suggest that chemokine-stimulated associations between Vav1, SLP-76, and ADAP facilitate Rac1 activation and alpha4beta1-mediated adhesion, whereas Pyk2 opposes this adhesion by limiting Rac1 activation. (PMID:26202465)
• A distinct set of proteins interaction partners required for chemokine-directed T cell migration is attracted by phosphotyrosine 571 of ADAP, including ZAP70. (PMID:26246585)
• Current knowledge of the functions of the adapter protein ADAP in T cell signaling with a focus on the role of individual phosphotyrosine (pY) motifs for SH2 domain mediated interactions is presented. (PMID:27258783)
• results of this study indicate that a novel T cell adaptor protein, activation-dependent, raft-recruited ADAP-like phosphoprotein (ARAP), plays a unique role in T cells as a part of both the proximal activation signaling and inside-out signaling pathways that result in integrin activation and T cell adhesion (PMID:27335501)
• Ubc9 is an essential regulator of ADAP where it is required for TCR-induced membrane recruitment of the small GTPase Rap1 and its effector protein RapL and for activation of the small GTPase Rac1 in T cell adhesion. (PMID:29127148)
• Findings reveal that ADAP acts upstream of SLP-76 to convert labile, Ca(2+)-competent microclusters into stable adhesive junctions with enhanced signaling potential. (PMID:30305305)
• The Multiple Roles of the Cytosolic Adapter Proteins ADAP, SKAP1 and SKAP2 for TCR/CD3 -Mediated Signaling Events. (PMID:34295339)
• FYB methylation in peripheral blood as a potential marker for the early-stage lung cancer: a case-control study in Chinese population. (PMID:34882057)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fyb1b	ENSDARG00000044694
danio_rerio	fyb1a	ENSDARG00000094764
mus_musculus	Fyb1	ENSMUSG00000022148
rattus_norvegicus	Fyb1	ENSRNOG00000013886

Paralogs (2): PRAM1 (ENSG00000133246), FYB2 (ENSG00000187889)

Protein

Protein identifiers

FYN-binding protein 1 — O15117 (reviewed: O15117)

Alternative names: Adhesion and degranulation promoting adaptor protein, FYB-120/130, FYN-T-binding protein, SLAP-130, SLP-76-associated phosphoprotein

All UniProt accessions (6): O15117, A0A2R8YEE1, D6RAE8, D6RC38, D6RER7, D6RFJ5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells. May play a role in linking T-cell signaling to remodeling of the actin cytoskeleton. Modulates the expression of IL2. Involved in platelet activation. Prevents the degradation of SKAP1 and SKAP2. May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells.

Subunit / interactions. Part of a complex consisting of SKAP2, FYB1 and PTPNS1. Part of a complex consisting of SKAP2, FYB1 and LILRB3. Part of a complex consisting of SKAP1, FYB1 and CLNK. Interacts with CLNK (via its SH2 domain); this interaction allows SKAP1 and FYB1 to recruit FYN to the complex, thus promoting the phosphorylation of CLNK by FYN. Interacts with FYN. Interacts with LCP2. Interacts with SKAP1. Interacts with SKAP2. Interacts with FASLG. Interacts with EVL. Interacts with TMEM47. Interacts with LCK.

Subcellular location. Cytoplasm. Nucleus. Cell junction.

Tissue specificity. Expressed in hematopoietic tissues such as myeloid and T-cells, spleen and thymus. Not expressed in B-cells, nor in non-lymphoid tissues.

Post-translational modifications. T-cell receptor ligation leads to increased tyrosine phosphorylation.

Disease relevance. Thrombocytopenia 3 (THC3) [MIM:273900] A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC3 is an autosomal recessive form characterized by onset in infancy. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
O15117-1	FYB-120	yes
O15117-2	FYB-130
O15117-3	3

RefSeq proteins (5): NP_001230022, NP_001336262, NP_001456, NP_061064, NP_955367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR029294	hSH3	Domain
IPR035540	FYB_hSH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR043443	FYB1/2-like	Family

Pfam: PF07653, PF14603

UniProt features (61 total): compositionally biased region 12, modified residue 10, strand 9, sequence conflict 6, short sequence motif 5, helix 5, sequence variant 4, region of interest 3, domain 2, splice variant 2, chain 1, turn 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1RI9	SOLUTION NMR
2GTJ	SOLUTION NMR
2GTO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15117-F1	57.50	0.14

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 (10): 3, 28, 46, 225, 329, 457, 571, 573, 580, 651

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-202433	Generation of second messenger molecules
R-HSA-391160	Signal regulatory protein family interactions

MSigDB gene sets: 309 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, MCLACHLAN_DENTAL_CARIES_UP, GNF2_CASP8, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, MODULE_45, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, DOANE_RESPONSE_TO_ANDROGEN_DN, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, MODULE_165, AFFAR_YY1_TARGETS_UP

GO Biological Process (4): immune response (GO:0006955), integrin-mediated signaling pathway (GO:0007229), T cell receptor signaling pathway (GO:0050852), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (3): signaling receptor binding (GO:0005102), lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytosol (GO:0005829), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), protein-containing complex (GO:0032991), anchoring junction (GO:0070161), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TCR signaling	1
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway	1
antigen receptor-mediated signaling pathway	1
protein localization to membrane	1
protein localization to cell periphery	1
protein binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
membrane	1
cell periphery	1
cytoskeleton	1
cellular_component	1
cell junction	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1764 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FYB1	LCP2	Q13094	998
FYB1	SKAP1	Q86WV1	993
FYB1	VAV1	P15498	941
FYB1	SKAP2	O75563	935
FYB1	GRAP2	O75791	929
FYB1	APBB1IP	Q7Z5R6	895
FYB1	FYN	P06241	868
FYB1	CARD11	Q9BXL7	814
FYB1	ACKR1	Q16570	807
FYB1	NCK1	P16333	803
FYB1	GRB2	P29354	777
FYB1	LCK	P06239	764
FYB1	BCL10	O95999	732
FYB1	RASSF5	Q8WWW0	719
FYB1	GRAP	Q13588	711

IntAct

43 interactions, top by confidence:

A	B	Type	Score
FYB1	LCP2	psi-mi:“MI:0915”(physical association)	0.900
LCP2	FYB1	psi-mi:“MI:0915”(physical association)	0.900
LCP2	FYB1	psi-mi:“MI:0914”(association)	0.900
LCP2	FYB1	psi-mi:“MI:0407”(direct interaction)	0.900
FYN	FYB1	psi-mi:“MI:0915”(physical association)	0.820
FYN	FYB1	psi-mi:“MI:0914”(association)	0.820
FYN	FYB1	psi-mi:“MI:0407”(direct interaction)	0.820
FYB1	SKAP1	psi-mi:“MI:0915”(physical association)	0.730
FYB1	SKAP1	psi-mi:“MI:0407”(direct interaction)	0.730
SKAP1	FYB1	psi-mi:“MI:0915”(physical association)	0.730
FYB1	NCK2	psi-mi:“MI:0915”(physical association)	0.620
NCK2	FYB1	psi-mi:“MI:0915”(physical association)	0.620
FYB1	NCK2	psi-mi:“MI:0914”(association)	0.620
NCK1	FYB1	psi-mi:“MI:0915”(physical association)	0.560
SH2D1A	FYB1	psi-mi:“MI:0407”(direct interaction)	0.530
FYB1	SH2D1A	psi-mi:“MI:0915”(physical association)	0.530
FYN	FYB1	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (41): FYN (Two-hybrid), LCP2 (Two-hybrid), NCK2 (Two-hybrid), UBE2I (Affinity Capture-Western), FYB (Affinity Capture-Western), FYB (Affinity Capture-Western), UBE2I (Affinity Capture-MS), SKAP1 (Two-hybrid), FYB (Proximity Label-MS), SKAP2 (PCA), HIST2H2BE (Proximity Label-MS), FYB (Affinity Capture-Western), FYB (Reconstituted Complex), SKAP1 (Reconstituted Complex), SKAP1 (Two-hybrid)

ESM2 similar proteins: A1X283, A2AAY5, A5D7F8, A5GFW5, A6ND36, D3ZIE4, D3ZUI5, E2RP94, M0R4F8, O15117, O35601, O54967, O75128, O89032, Q04584, Q06649, Q07912, Q13094, Q13625, Q15942, Q17R10, Q17R13, Q1LYG0, Q32LQ1, Q3TC93, Q3UH68, Q498M5, Q4KM52, Q5DTU0, Q5JV73, Q5NBX1, Q5TCZ1, Q5U2X5, Q62523, Q6IQ23, Q6TXD4, Q80TI1, Q8BI17, Q8BZI0, Q8CG79

Diamond homologs: A2A995, D3ZIE4, O15117, O35601, Q5VWT5, Q6BCL1, Q96QH2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FYN	“up-regulates activity”	FYB1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	142
Likely benign	28
Benign	47

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
417970	NM_001465.6(FYB1):c.1385_1386del (p.Thr461_Tyr462insTer)	Pathogenic
417971	NM_001465.6(FYB1):c.393G>A (p.Trp131Ter)	Pathogenic

SpliceAI

3269 predictions. Top by Δscore:

Variant	Effect	Δscore
5:39108263:C:CC	acceptor_gain	1.0000
5:39110354:A:AC	donor_gain	1.0000
5:39110355:C:CC	donor_gain	1.0000
5:39118867:GACTT:G	donor_loss	1.0000
5:39118868:ACTTA:A	donor_loss	1.0000
5:39118869:CTTA:C	donor_loss	1.0000
5:39118870:TTACA:T	donor_loss	1.0000
5:39118871:TAC:T	donor_loss	1.0000
5:39118872:A:AC	donor_gain	1.0000
5:39118873:C:A	donor_loss	1.0000
5:39118873:C:CC	donor_gain	1.0000
5:39118873:CATTT:C	donor_gain	1.0000
5:39119032:TCATA:T	acceptor_gain	1.0000
5:39119033:CATA:C	acceptor_gain	1.0000
5:39119033:CATAC:C	acceptor_gain	1.0000
5:39119034:ATAC:A	acceptor_loss	1.0000
5:39119035:TA:T	acceptor_gain	1.0000
5:39119037:C:CC	acceptor_gain	1.0000
5:39119038:T:C	acceptor_loss	1.0000
5:39119533:A:AC	donor_gain	1.0000
5:39119534:C:CC	donor_gain	1.0000
5:39119546:T:A	donor_gain	1.0000
5:39119630:CTTGA:C	acceptor_gain	1.0000
5:39119635:C:CC	acceptor_gain	1.0000
5:39119642:G:T	acceptor_gain	1.0000
5:39119644:C:CT	acceptor_gain	1.0000
5:39119645:A:T	acceptor_gain	1.0000
5:39119649:C:CT	acceptor_gain	1.0000
5:39122400:TGT:T	acceptor_gain	1.0000
5:39122403:C:CC	acceptor_gain	1.0000

AlphaMissense

5454 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:39110380:A:T	V758D	1.000
5:39134346:C:T	G560D	1.000
5:39134875:C:T	G552D	1.000
5:39134878:A:G	L551S	1.000
5:39134880:C:A	W550C	1.000
5:39134880:C:G	W550C	1.000
5:39134882:A:G	W550R	1.000
5:39134882:A:T	W550R	1.000
5:39134908:C:G	R541P	1.000
5:39110386:C:T	G756D	0.999
5:39110387:C:G	G756R	0.999
5:39118893:G:C	C748W	0.999
5:39118895:A:G	C748R	0.999
5:39118957:A:G	L727P	0.999
5:39119538:A:C	F699L	0.999
5:39119538:A:T	F699L	0.999
5:39119540:A:G	F699L	0.999
5:39134325:A:T	V567E	0.999
5:39134340:A:T	I562N	0.999
5:39134346:C:A	G560V	0.999
5:39134347:C:G	G560R	0.999
5:39134876:C:G	G552R	0.999
5:39134878:A:C	L551W	0.999
5:39134881:C:G	W550S	0.999
5:39134895:G:C	N545K	0.999
5:39134895:G:T	N545K	0.999
5:39134909:G:T	R541S	0.999
5:39134914:A:C	I539S	0.999
5:39134914:A:G	I539T	0.999
5:39134914:A:T	I539N	0.999

dbSNP variants (sampled 300 via entrez): RS1000010838 (5:39252466 A>C,G), RS1000080647 (5:39128423 T>A), RS1000091338 (5:39133320 G>A), RS1000091827 (5:39175504 G>A), RS1000163903 (5:39230662 G>C), RS1000191716 (5:39208717 C>T), RS1000198575 (5:39128606 A>T), RS1000200637 (5:39169704 G>A), RS1000209425 (5:39163251 A>C), RS1000226700 (5:39109836 T>C), RS1000278718 (5:39116092 T>C), RS1000281880 (5:39240490 C>T), RS1000307141 (5:39170081 C>A,T), RS1000309138 (5:39208490 G>A), RS1000320267 (5:39225498 T>C)

Disease associations

OMIM: gene MIM:602731 | disease phenotypes: MIM:273900

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombocytopenia 3	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
thrombocytopenia 3	Moderate	AR

Mondo (1): thrombocytopenia 3 (MONDO:0010120)

Orphanet (1): Hereditary thrombocytopenia with normal platelets (Orphanet:268322)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000967	Petechiae
HP:0000979	Purpura
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001892	Abnormal bleeding
HP:0003010	Prolonged bleeding time
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0005537	Decreased mean platelet volume
HP:0005548	Megakaryocytopenia
HP:0007420	Spontaneous hematomas
HP:0011463	Childhood onset
HP:0012143	Abnormal megakaryocyte morphology

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003043_72	Inflammatory bowel disease	2.000000e-20
GCST003044_153	Crohn’s disease	2.000000e-16
GCST003045_99	Ulcerative colitis	9.000000e-12
GCST003518_45	Daytime sleep phenotypes	3.000000e-06
GCST003804_2	Non-response to bupropion and depression	5.000000e-07
GCST006427_51	Depression in smokers	4.000000e-06
GCST009028_50	Adverse response to drug	6.000000e-07
GCST012034_5	Sleep (1/2-day periodicity)	2.000000e-10
GCST90002401_157	Platelet distribution width	2.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0009658	adverse effect
EFO:0007984	platelet component distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567487	Thrombocytopenia 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066316 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects expression, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	decreases expression	2
Air Pollutants	decreases expression, affects expression, increases abundance	2
Silicon Dioxide	increases expression, decreases expression	2
mivebresib	decreases expression	1
bisphenol A	decreases methylation	1
terbufos	decreases methylation	1
3,4-dichloroaniline	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
bathocuproine sulfonate	affects cotreatment, decreases expression, decreases reaction	1
cupric chloride	decreases expression	1
vanadyl sulfate	decreases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
clothianidin	decreases expression	1
abrine	increases expression	1
Irinotecan	decreases expression	1
Zoledronic Acid	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Diuron	increases expression	1
Fonofos	decreases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5665347	Binding	Inhibition of T-Fyn (unknown origin) by HTRF assay	Discovery of the SMYD3 Inhibitor BAY-6035 Using Thermal Shift Assay (TSA)-Based High-Throughput Screening. — SLAS Discov

Clinical trials (associated diseases)

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