C17orf99

Summary

C17orf99 (chromosome 17 open reading frame 99, HGNC:34490) is a protein-coding gene on chromosome 17q25.3, encoding Protein IL-40 (Q6UX52). Probable B cell-associated cytokine that plays a role in the regulation of humoral immune responses.

Predicted to enable transmembrane signaling receptor activity. Predicted to be involved in cell surface receptor signaling pathway; mature B cell differentiation involved in immune response; and positive regulation of immunoglobulin production in mucosal tissue. Located in extracellular space.

Source: NCBI Gene 100141515 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 5 total
• MANE Select transcript: NM_001163075

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34490
Approved symbol	C17orf99
Name	chromosome 17 open reading frame 99
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	GLPG464, UNQ464, IL-40
Ensembl gene	ENSG00000187997
Ensembl biotype	protein_coding
Entrez	100141515

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000340363, ENST00000451352, ENST00000586029, ENST00000586246, ENST00000586999, ENST00000591995

RefSeq mRNA: 1 — MANE Select: NM_001163075 NM_001163075

CCDS: CCDS54171

Canonical transcript exons

ENST00000340363 — 5 exons

Exon	Start	End
ENSE00001370695	78165889	78166297
ENSE00001375320	78164095	78164364
ENSE00001387291	78146385	78146444
ENSE00001389129	78146879	78146911
ENSE00003463217	78160955	78161254

Expression profiles

Bgee: expression breadth ubiquitous, 111 present calls, max score 94.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5091 / max 42.8301, expressed in 78 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163031	0.5091	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	94.33	gold quality
buccal mucosa cell	CL:0002336	90.33	gold quality
trabecular bone tissue	UBERON:0002483	89.34	gold quality
oocyte	CL:0000023	88.77	gold quality
secondary oocyte	CL:0000655	85.78	gold quality
bone marrow	UBERON:0002371	82.31	gold quality
bone marrow cell	CL:0002092	79.53	gold quality
amniotic fluid	UBERON:0000173	67.29	gold quality
gingival epithelium	UBERON:0001949	64.93	gold quality
blood	UBERON:0000178	64.73	gold quality
tendon of biceps brachii	UBERON:0008188	62.61	silver quality
epithelium of nasopharynx	UBERON:0001951	62.34	gold quality
gingiva	UBERON:0001828	60.60	gold quality
superficial temporal artery	UBERON:0001614	59.69	gold quality
esophagus squamous epithelium	UBERON:0006920	59.35	gold quality
vena cava	UBERON:0004087	58.86	gold quality
endothelial cell	CL:0000115	57.75	gold quality
granulocyte	CL:0000094	57.44	gold quality
mucosa of transverse colon	UBERON:0004991	57.26	gold quality
tonsil	UBERON:0002372	55.79	gold quality
myocardium	UBERON:0002349	55.76	gold quality
thymus	UBERON:0002370	55.50	gold quality
medial globus pallidus	UBERON:0002477	54.83	gold quality
vermiform appendix	UBERON:0001154	54.27	gold quality
parietal pleura	UBERON:0002400	54.15	gold quality
visceral pleura	UBERON:0002401	53.45	gold quality
skin of abdomen	UBERON:0001416	52.97	gold quality
lymph node	UBERON:0000029	52.90	gold quality
oral cavity	UBERON:0000167	52.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	52.38	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	37.97
E-MTAB-9067	yes	4.02
E-HCAD-10	yes	3.22
E-ANND-3	no	2.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting C17orf99, 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-577	99.78	69.13	2479
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-3145-5P	98.57	67.83	900
HSA-MIR-10397-3P	97.78	65.70	601
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-585-5P	97.54	69.02	955
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-3529-5P	97.12	67.06	440

Literature-anchored findings (GeneRIF, showing 4)

• these observations indicate that C17orf99 encodes a novel B cell-associated cytokine, which we have called IL-40, that plays an important role in humoral immune responses and may also play a role in B cell development. (PMID:28978694)
• A novel intergenic variant, rs2004339 A/G, of the gene encoding interleukin-40, C17orf99, is associated with risk of rheumatoid arthritis in Iraqi women. (PMID:37951185)
• Molecular landscape of the interleukin-40 encoding gene, C17orf99, in patients with acute myeloid leukemia. (PMID:38286266)
• IL-40 is up-regulated in the synovial fluid and cartilage of osteoarthritis patients and contributes to the alteration of chondrocytes phenotype in vitro. (PMID:39080724)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	6030468B19Rik	ENSMUSG00000025573
rattus_norvegicus	C10h17orf99	ENSRNOG00000045889

Paralogs (17): FCGR2B (ENSG00000072694), FCRLA (ENSG00000132185), FCRL2 (ENSG00000132704), FCGR2A (ENSG00000143226), FCRL5 (ENSG00000143297), FCGR1A (ENSG00000150337), FCRL3 (ENSG00000160856), FCRLB (ENSG00000162746), FCGR3B (ENSG00000162747), FCRL4 (ENSG00000163518), FCRL1 (ENSG00000163534), FCER1A (ENSG00000179639), FCRL6 (ENSG00000181036), FCGR3A (ENSG00000203747), FCGR2C (ENSG00000244682), PECAM1 (ENSG00000261371), MILR1 (ENSG00000271605)

Protein

Protein identifiers

Protein IL-40 — Q6UX52 (reviewed: Q6UX52)

Alternative names: Interleukin-40

All UniProt accessions (3): Q6UX52, A0A0D9SGD8, K7ELL6

UniProt curated annotations — full annotation on UniProt →

Function. Probable B cell-associated cytokine that plays a role in the regulation of humoral immune responses. Involved in lymphocyte B cell development and immunoglobulin/IgA production.

Subcellular location. Secreted.

Tissue specificity. Expressed in fetal liver and bone marrow. Expressed in peripheral blood lymphocyte B cells.

RefSeq proteins (1): NP_001156547* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR040878	IL-40-like_Ig	Domain

Pfam: PF17736

UniProt features (5 total): glycosylation site 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX52-F1	73.46	0.40

Functional residue map

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

Glycosylation sites (2): 86, 132

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_ORGAN_OR_TISSUE_SPECIFIC_IMMUNE_RESPONSE, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_IMMUNOGLOBULIN_PRODUCTION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_IMMUNOGLOBULIN_PRODUCTION, GOBP_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (6): adaptive immune response (GO:0002250), mature B cell differentiation involved in immune response (GO:0002313), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), positive regulation of immunoglobulin production in mucosal tissue (GO:2000558), immune system process (GO:0002376)

GO Molecular Function (2): transmembrane signaling receptor activity (GO:0004888), cytokine activity (GO:0005125)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), external side of plasma membrane (GO:0009897), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	2
B cell activation involved in immune response	1
mature B cell differentiation	1
immune system process	1
response to stimulus	1
signal transduction	1
immunoglobulin production in mucosal tissue	1
positive regulation of immunoglobulin production	1
positive regulation of immunoglobulin mediated immune response	1
regulation of immunoglobulin production in mucosal tissue	1
biological_process	1
signaling receptor activity	1
receptor ligand activity	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

160 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C17orf99	GAGE12H	A6NDE8	400
C17orf99	BNIP5	P0C671	372
C17orf99	SYNGR2	O43760	366
C17orf99	LYSMD1	Q96S90	357
C17orf99	TMEM235	A6NFC5	348
C17orf99	BLVRB	P30043	302
C17orf99	ASB12	Q8WXK4	294
C17orf99	C5orf46	Q6UWT4	290
C17orf99	IL4	P05112	288
C17orf99	FCRL2	Q96LA5	288
C17orf99	GOLGA6A	Q9NYA3	286
C17orf99	FAM180B	Q6P0A1	277
C17orf99	MOB3C	Q70IA8	275
C17orf99	METRNL	Q641Q3	272
C17orf99	IL1F10	Q8WWZ1	270

IntAct

0 interactions, top by confidence:

BioGRID (1): C17orf99 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0K2S4Q6, A6NI73, B6A8C7, G1TR84, O43699, O75019, O75022, O75023, O75871, P0C191, P24071, P31994, P40198, P43629, P43630, P59901, P97484, Q08708, Q14943, Q28110, Q496F6, Q6GTX8, Q6ISS4, Q6PI73, Q6UX52, Q863H2, Q8C567, Q8IYS5, Q8K249, Q8MJZ2, Q8MJZ7, Q8N109, Q8N149, Q8N423, Q8N6C8, Q8N743, Q8NHJ6, Q8NHK3, Q8NHL6, Q8VBT3

Diamond homologs: Q6UX52, Q9CX63

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

992 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78160935:T:TA	acceptor_gain	0.9900
17:78146445:GTGAG:G	donor_loss	0.9800
17:78146447:GAGTC:G	donor_loss	0.9800
17:78146459:G:T	donor_gain	0.9800
17:78147143:G:T	donor_gain	0.9800
17:78160936:G:A	acceptor_gain	0.9800
17:78161073:T:TA	acceptor_gain	0.9800
17:78161241:G:GT	donor_gain	0.9800
17:78161255:G:GG	donor_gain	0.9800
17:78146443:GG:G	donor_gain	0.9700
17:78146444:GG:G	donor_gain	0.9700
17:78146448:AGTC:A	donor_loss	0.9700
17:78146877:A:AG	acceptor_gain	0.9700
17:78146878:G:GG	acceptor_gain	0.9700
17:78161250:GTCCA:G	donor_gain	0.9700
17:78146440:GCTGG:G	donor_gain	0.9600
17:78146445:G:GG	donor_gain	0.9600
17:78146910:AGGTA:A	donor_loss	0.9600
17:78146912:G:GA	donor_loss	0.9600
17:78146913:T:G	donor_loss	0.9600
17:78161214:GGAC:G	donor_gain	0.9600
17:78161226:GC:G	donor_gain	0.9600
17:78164132:GGACA:G	acceptor_gain	0.9600
17:78165886:AAGGT:A	acceptor_gain	0.9600
17:78164089:T:TA	acceptor_gain	0.9500
17:78164131:A:AG	acceptor_gain	0.9500
17:78164132:G:GG	acceptor_gain	0.9500
17:78160954:GAA:G	acceptor_gain	0.9400
17:78164085:A:AG	acceptor_gain	0.9400
17:78164091:CCAG:C	acceptor_gain	0.9400

AlphaMissense

1735 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78161131:T:C	F83L	0.935
17:78161133:C:A	F83L	0.935
17:78161133:C:G	F83L	0.935
17:78160999:T:C	F39L	0.885
17:78161001:C:A	F39L	0.885
17:78161001:C:G	F39L	0.885
17:78164268:T:C	F182L	0.845
17:78164270:C:A	F182L	0.845
17:78164270:C:G	F182L	0.845
17:78161218:A:C	S112R	0.828
17:78161220:T:A	S112R	0.828
17:78161220:T:G	S112R	0.828
17:78164121:T:C	F133L	0.827
17:78164123:C:A	F133L	0.827
17:78164123:C:G	F133L	0.827
17:78161179:T:C	F99L	0.795
17:78161181:C:A	F99L	0.795
17:78161181:C:G	F99L	0.795
17:78161024:T:C	I47T	0.788
17:78164184:A:C	S154R	0.776
17:78164186:C:A	S154R	0.776
17:78164186:C:G	S154R	0.776
17:78164301:T:C	F193L	0.771
17:78164303:C:A	F193L	0.771
17:78164303:C:G	F193L	0.771
17:78164274:T:C	F184L	0.748
17:78164276:C:A	F184L	0.748
17:78164276:C:G	F184L	0.748
17:78146890:T:C	F17L	0.715
17:78146892:C:A	F17L	0.715

dbSNP variants (sampled 300 via entrez): RS1000005612 (17:78157525 G>A,C,T), RS1000189467 (17:78152915 C>T), RS1000583088 (17:78163653 C>T), RS1000691176 (17:78151911 T>C), RS1000830242 (17:78162135 G>A,T), RS1000832527 (17:78147114 T>C), RS1000963037 (17:78156966 G>A,C), RS1001233393 (17:78152817 C>T), RS1001285721 (17:78152543 C>T), RS1001348233 (17:78152523 T>C), RS1001475286 (17:78147800 T>A,C,G), RS1001806232 (17:78162867 C>A,G,T), RS1001837230 (17:78163155 G>A), RS1001841231 (17:78147591 C>T), RS1002238981 (17:78151582 C>T)

Disease associations

OMIM: gene `` | 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

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	1
beta-lapachone	decreases expression	1
aflatoxin B2	decreases methylation	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation, increases methylation	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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