THEMIS

Summary

THEMIS (thymocyte selection associated, HGNC:21569) is a protein-coding gene on chromosome 6q22.33, encoding Protein THEMIS (Q8N1K5). Plays a central role in late thymocyte development by controlling both positive and negative T-cell selection.

This gene encodes a protein that plays a regulatory role in both positive and negative T-cell selection during late thymocyte development. The protein functions through T-cell antigen receptor signaling, and is necessary for proper lineage commitment and maturation of T-cells. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 387357 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 106 total
• MANE Select transcript: NM_001010923

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21569
Approved symbol	THEMIS
Name	thymocyte selection associated
Location	6q22.33
Locus type	gene with protein product
Status	Approved
Aliases	bA325O24.4, FLJ40584, bA325O24.3, THEMIS1
Ensembl gene	ENSG00000172673
Ensembl biotype	protein_coding
OMIM	613607
Entrez	387357

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000368248, ENST00000368250, ENST00000434358, ENST00000537166, ENST00000626040, ENST00000630369, ENST00000852157

RefSeq mRNA: 7 — MANE Select: NM_001010923 NM_001010923, NM_001164685, NM_001164687, NM_001318531, NM_001394520, NM_001394521, NM_001394522

CCDS: CCDS34534, CCDS55055, CCDS55056

Canonical transcript exons

ENST00000368248 — 6 exons

Exon	Start	End
ENSE00001084554	127719688	127719823
ENSE00001179249	127812883	127813931
ENSE00001179254	127829476	127829934
ENSE00003599310	127855030	127855188
ENSE00003923719	127708200	127710016
ENSE00003936109	127900842	127901058

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 82.86.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4701 / max 460.8167, expressed in 215 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75452	3.8293	157
75455	0.6040	77
75454	0.3740	66
75456	0.2459	57
75450	0.2379	39
75453	0.1738	57
75449	0.0052	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	82.86	gold quality
granulocyte	CL:0000094	77.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.04	gold quality
vermiform appendix	UBERON:0001154	75.23	gold quality
blood	UBERON:0000178	75.03	gold quality
primary visual cortex	UBERON:0002436	73.90	gold quality
colonic epithelium	UBERON:0000397	71.93	gold quality
superior frontal gyrus	UBERON:0002661	70.73	gold quality
prefrontal cortex	UBERON:0000451	70.64	gold quality
tonsil	UBERON:0002372	70.27	gold quality
duodenum	UBERON:0002114	69.45	gold quality
bone marrow cell	CL:0002092	69.16	gold quality
gall bladder	UBERON:0002110	68.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	67.19	gold quality
bone marrow	UBERON:0002371	65.93	gold quality
rectum	UBERON:0001052	65.53	gold quality
frontal cortex	UBERON:0001870	65.20	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	64.94	gold quality
spleen	UBERON:0002106	64.17	gold quality
cerebral cortex	UBERON:0000956	62.01	gold quality
anterior cingulate cortex	UBERON:0009835	62.00	gold quality
small intestine	UBERON:0002108	58.65	gold quality
smooth muscle tissue	UBERON:0001135	58.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	57.31	gold quality
right frontal lobe	UBERON:0002810	56.34	gold quality
lung	UBERON:0002048	55.91	gold quality
corpus callosum	UBERON:0002336	55.54	gold quality
mucosa of transverse colon	UBERON:0004991	55.07	gold quality
endometrium	UBERON:0001295	54.64	gold quality
upper lobe of left lung	UBERON:0008952	54.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

124 targeting THEMIS, 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-5692A	100.00	74.40	6850
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 11)

• Functional characterization of the homologous mouse gene. (PMID:19597498)
• Functional analysis of the mouse gene by knockout, and comparison of the mouse and human proteins. (PMID:19597499)
• specific role for THEMIS in early TCR signalosome function (PMID:21189249)
• SPOP mutations may define a new molecular subtype of prostate cancer. (PMID:22610119)
• Themis1 exhibits the same potential to restore T cell development and T cell receptor-mediated signaling in Themis1-deficient mice. (PMID:22732588)
• THEMIS binding to GRB2 was required for thymocyte development. (PMID:23460737)
• THEMIS showed higher mRNA expression in active celiac disease compared with treated patients and controls. (PMID:23820479)
• the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T-cell survival. (PMID:25535246)
• we have demonstrated mutually exclusive use of exon 1 and 2 amongst 16 novel THEMIS isoforms. We also show inverse correlation between THEMIS expression in human CD4+ T-cells and dosage of the multiple sclerosis risk allele at rs13204742, driven by reduced expression of exon 1- containing isoforms (PMID:27438997)
• we found that THEMIS directly regulated the catalytic activity of the tyrosine phosphatase SHP-1. (PMID:28250424)
• THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells (PMID:32004441)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	themis	ENSDARG00000010619
mus_musculus	Themis	ENSMUSG00000049109
rattus_norvegicus	Themis	ENSRNOG00000014979

Paralogs (1): THEMIS2 (ENSG00000130775)

Protein

Protein identifiers

Protein THEMIS — Q8N1K5 (reviewed: Q8N1K5)

Alternative names: Thymocyte-expressed molecule involved in selection

All UniProt accessions (3): Q8N1K5, A0A0D9SFD2, X1WI26

UniProt curated annotations — full annotation on UniProt →

Function. Plays a central role in late thymocyte development by controlling both positive and negative T-cell selection. Required to sustain and/or integrate signals required for proper lineage commitment and maturation of T-cells. Regulates T-cell development through T-cell antigen receptor (TCR) signaling and in particular through the regulation of calcium influx and phosphorylation of Erk.

Subunit / interactions. Interacts with PLCG1, ITK, GRB2, and LAT.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated on Tyr residues quickly after TCR stimulation.

Similarity. Belongs to the themis family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N1K5-1	1	yes
Q8N1K5-2	2
Q8N1K5-3	3
Q8N1K5-4	4

RefSeq proteins (7): NP_001010923, NP_001158157, NP_001158159, NP_001305460, NP_001381449, NP_001381450, NP_001381451 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025946	CABIT_dom	Domain
IPR039671	THEMIS	Family

Pfam: PF12736

UniProt features (15 total): sequence conflict 5, region of interest 3, splice variant 3, sequence variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9UOU	X-RAY DIFFRACTION	3.06
9IAZ	ELECTRON MICROSCOPY	3.2
9I3P	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N1K5-F1	76.26	0.28

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 (1): 584

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 175 (showing top): GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_T_CELL_SELECTION, GOBP_ADAPTIVE_IMMUNE_RESPONSE, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_T_CELL_SELECTION, GOCC_CELL_CELL_JUNCTION, GOBP_T_CELL_SELECTION, GAVIN_FOXP3_TARGETS_CLUSTER_P3, GAVIN_FOXP3_TARGETS_CLUSTER_P4, ZHENG_BOUND_BY_FOXP3, MARSON_BOUND_BY_FOXP3_STIMULATED, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOCC_COP9_SIGNALOSOME

GO Biological Process (5): adaptive immune response (GO:0002250), positive T cell selection (GO:0043368), negative T cell selection (GO:0043383), T cell receptor signaling pathway (GO:0050852), immune system process (GO:0002376)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cell-cell junction (GO:0005911), COP9 signalosome (GO:0008180)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell selection	2
immune response	1
antigen receptor-mediated signaling pathway	1
biological_process	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
anchoring junction	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

516 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THEMIS	GRB2	P29354	565
THEMIS	PTPN11	Q06124	552
THEMIS	HBZ	P02008	544
THEMIS	PTPRK	Q15262	510
THEMIS	TESPA1	A2RU30	480
THEMIS	TIFA	Q96CG3	462
THEMIS	LCP2	Q13094	449
THEMIS	PLCG1	P19174	406
THEMIS	KIAA0408	Q6ZU52	404
THEMIS	SELL	P14151	401
THEMIS	RAG1	P15918	398
THEMIS	SRC	P12931	355
THEMIS	SEC63	Q9UGP8	348
THEMIS	GRAP2	O75791	334
THEMIS	MTCL3	Q5TF21	323

IntAct

20 interactions, top by confidence:

A	B	Type	Score
THEMIS	GRB2	psi-mi:“MI:0914”(association)	0.840
THEMIS	GRB2	psi-mi:“MI:0915”(physical association)	0.840
HBZ	THEMIS	psi-mi:“MI:0915”(physical association)	0.540
THEMIS	HBZ	psi-mi:“MI:0914”(association)	0.540
HBZ	THEMIS	psi-mi:“MI:0403”(colocalization)	0.540
THEMIS	PRMT6	psi-mi:“MI:0915”(physical association)	0.510
THEMIS	PTPN6	psi-mi:“MI:0914”(association)	0.500
PTPN6	THEMIS	psi-mi:“MI:0915”(physical association)	0.500
THEMIS	PLCG1	psi-mi:“MI:0914”(association)	0.460
THEMIS	LAT	psi-mi:“MI:0914”(association)	0.460
LAT	GRB2	psi-mi:“MI:0914”(association)	0.350
THEMIS	POTEF	psi-mi:“MI:0914”(association)	0.350
THEMIS	ALOX5	psi-mi:“MI:0914”(association)	0.350
cutA	THEMIS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): PTPN11 (Affinity Capture-MS), GRB2 (Affinity Capture-MS), POTEF (Affinity Capture-MS), POTEF (Affinity Capture-MS), GRB2 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PRMT6 (Affinity Capture-Luminescence), PRMT6 (Two-hybrid)

ESM2 similar proteins: A4D1B5, A5D789, A5PF62, B1ANS9, B2GV47, D3YVL2, D3ZSP7, O00443, O70167, O70173, O75747, O88196, P53804, Q14D04, Q1LVQ2, Q3TCV3, Q3TUL7, Q402B2, Q4R8X0, Q4R9E9, Q4VA55, Q5H9S7, Q5R4M2, Q5RAY1, Q5RB52, Q5RBH9, Q5T0N1, Q5U228, Q5ZKI7, Q61194, Q6NU22, Q6NU51, Q6P2C0, Q6ZUJ8, Q8BGW0, Q8C779, Q8CDN1, Q8IXR9, Q8N1K5, Q8NB91

Diamond homologs: A5D789, A5PF62, Q5TEJ8, Q8BGW0, Q8N1K5, Q91YX0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2104 predictions. Top by Δscore:

Variant	Effect	Δscore
6:127719822:CG:C	acceptor_gain	1.0000
6:127812877:CCTTA:C	donor_loss	1.0000
6:127812878:CTTA:C	donor_loss	1.0000
6:127812879:TTACC:T	donor_loss	1.0000
6:127812880:TACCT:T	donor_loss	1.0000
6:127812881:ACCTT:A	donor_loss	1.0000
6:127812882:C:G	donor_loss	1.0000
6:127813932:C:CC	acceptor_gain	1.0000
6:127855024:CTGTA:C	donor_loss	1.0000
6:127855025:TGTA:T	donor_loss	1.0000
6:127855026:GTAC:G	donor_loss	1.0000
6:127855027:TA:T	donor_loss	1.0000
6:127855029:C:CG	donor_loss	1.0000
6:127918462:T:C	donor_gain	1.0000
6:127710012:TGTTT:T	acceptor_gain	0.9900
6:127710015:TT:T	acceptor_gain	0.9900
6:127710015:TTCT:T	acceptor_loss	0.9900
6:127710016:TCT:T	acceptor_loss	0.9900
6:127710017:C:CC	acceptor_gain	0.9900
6:127710017:C:CG	acceptor_loss	0.9900
6:127710018:T:A	acceptor_loss	0.9900
6:127719819:TGACG:T	acceptor_gain	0.9900
6:127719820:GACG:G	acceptor_gain	0.9900
6:127719821:ACGC:A	acceptor_loss	0.9900
6:127719824:C:CC	acceptor_gain	0.9900
6:127719825:T:G	acceptor_loss	0.9900
6:127782771:C:CT	acceptor_gain	0.9900
6:127813928:CGAA:C	acceptor_gain	0.9900
6:127813930:AAC:A	acceptor_loss	0.9900
6:127813931:ACTA:A	acceptor_loss	0.9900

AlphaMissense

4234 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:127813623:C:G	G340R	0.993
6:127829591:T:A	R198S	0.991
6:127829591:T:G	R198S	0.991
6:127813622:C:T	G340D	0.990
6:127829511:A:G	L225P	0.990
6:127813205:A:G	L479P	0.989
6:127813577:A:G	L355P	0.987
6:127813682:G:T	A320D	0.986
6:127813340:A:G	F434S	0.985
6:127855098:G:T	A61D	0.983
6:127813616:A:G	F342S	0.981
6:127813230:C:G	D471H	0.980
6:127813612:C:A	K343N	0.980
6:127813612:C:G	K343N	0.980
6:127813645:G:C	F332L	0.980
6:127813645:G:T	F332L	0.980
6:127813647:A:G	F332L	0.980
6:127813172:A:G	L490P	0.979
6:127813541:A:T	V367E	0.979
6:127813622:C:A	G340V	0.979
6:127813683:C:G	A320P	0.979
6:127813339:A:C	F434L	0.978
6:127813339:A:T	F434L	0.978
6:127813341:A:G	F434L	0.978
6:127813607:C:G	R345P	0.978
6:127813646:A:G	F332S	0.977
6:127813886:A:T	V252D	0.977
6:127829511:A:T	L225H	0.977
6:127829586:A:T	V200E	0.977
6:127829592:C:G	R198T	0.977

dbSNP variants (sampled 300 via entrez): RS1000026405 (6:127828020 A>G), RS1000044676 (6:127806568 T>C,G), RS1000044907 (6:127738727 G>A,C), RS1000066 (6:127918267 C>A,G,T), RS1000066316 (6:127770940 A>C,G), RS1000070907 (6:127853259 T>TA), RS1000072260 (6:127728978 AC>A,ACC), RS1000095783 (6:127780768 G>T), RS1000113035 (6:127834191 T>C), RS1000118504 (6:127771293 G>A), RS1000151029 (6:127871887 C>T), RS1000153243 (6:127895590 C>G,T), RS1000156584 (6:127904750 C>T), RS1000167225 (6:127701308 G>A), RS1000188616 (6:127735401 A>C)

Disease associations

OMIM: gene MIM:613607 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000612_24	Celiac disease	3.000000e-14
GCST001198_54	Multiple sclerosis	6.000000e-09
GCST001532_6	Immune response to smallpox vaccine (IL-6)	2.000000e-07
GCST001920_5	QRS duration	5.000000e-06
GCST002880_2	Recalcitrant atopic dermatitis	7.000000e-07
GCST003264_900	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST003264_969	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003944_14	Hepcidin/ferritin ratio	1.000000e-06
GCST003944_15	Hepcidin/ferritin ratio	4.000000e-06
GCST004132_4	Crohn’s disease	7.000000e-06
GCST006631_43	Nicotine dependence and major depression (severity of comorbidity)	4.000000e-06
GCST008489_19	Celiac disease	2.000000e-08
GCST008916_127	Asthma	1.000000e-11
GCST009597_161	Multiple sclerosis	1.000000e-09
GCST009798_84	Asthma	3.000000e-10
GCST012489_81	Heel bone mineral density x serum urate levels interaction	6.000000e-09
GCST90014325_3	Asthma	7.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:1000651	recalcitrant atopic dermatitis
EFO:0004713	FEV/FVC ratio
EFO:0007901	hepcidin:ferritin ratio
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Nickel	increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
Arsenic Trioxide	decreases expression	1
Diuron	decreases expression	1
Zinc	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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