TCF7L1

Summary

TCF7L1 (transcription factor 7 like 1, HGNC:11640) is a protein-coding gene on chromosome 2p11.2, encoding Transcription factor 7-like 1 (Q9HCS4). Participates in the Wnt signaling pathway.

This gene encodes a member of the T cell factor/lymphoid enhancer factor family of transcription factors. These transcription factors are activated by beta catenin, mediate the Wnt signaling pathway and are antagonized by the transforming growth factor beta signaling pathway. The encoded protein contains a high mobility group-box DNA binding domain and participates in the regulation of cell cycle genes and cellular senescence.

Source: NCBI Gene 83439 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal agammaglobulinemia (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 1,323 total — 22 pathogenic, 13 likely-pathogenic
• MANE Select transcript: NM_031283

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11640
Approved symbol	TCF7L1
Name	transcription factor 7 like 1
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000152284
Ensembl biotype	protein_coding
OMIM	604652
Entrez	83439

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000282111, ENST00000442813, ENST00000490744, ENST00000494519, ENST00000868102, ENST00000922942, ENST00000922943

RefSeq mRNA: 1 — MANE Select: NM_031283 NM_031283

CCDS: CCDS1971

Canonical transcript exons

ENST00000282111 — 12 exons

Exon	Start	End
ENSE00000963600	85133392	85133933
ENSE00000963601	85134016	85134079
ENSE00000963602	85134323	85134450
ENSE00001004496	85306452	85306559
ENSE00001004500	85304255	85304338
ENSE00001004504	85302484	85302616
ENSE00001004508	85307642	85307717
ENSE00001004509	85305260	85305403
ENSE00001004512	85306206	85306365
ENSE00001277395	85309029	85310387
ENSE00002477621	85303895	85303997
ENSE00003512768	85283495	85283578

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 92.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.5688 / max 456.9634, expressed in 1811 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178058	44.5688	1811
21201	7.1055	1266
178055	0.0066	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	92.32	gold quality
tibial artery	UBERON:0007610	92.32	gold quality
aorta	UBERON:0000947	91.59	gold quality
mucosa of stomach	UBERON:0001199	91.10	gold quality
ascending aorta	UBERON:0001496	90.88	gold quality
thoracic aorta	UBERON:0001515	90.86	gold quality
descending thoracic aorta	UBERON:0002345	90.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.68	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.64	gold quality
left lobe of thyroid gland	UBERON:0001120	90.63	gold quality
lower esophagus	UBERON:0013473	90.63	gold quality
endocervix	UBERON:0000458	90.59	gold quality
right lobe of thyroid gland	UBERON:0001119	90.43	gold quality
right coronary artery	UBERON:0001625	90.32	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.27	gold quality
body of uterus	UBERON:0009853	89.67	gold quality
thyroid gland	UBERON:0002046	89.61	gold quality
left coronary artery	UBERON:0001626	89.42	gold quality
right ovary	UBERON:0002118	89.38	gold quality
omental fat pad	UBERON:0010414	89.01	gold quality
coronary artery	UBERON:0001621	88.98	gold quality
peritoneum	UBERON:0002358	88.93	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.91	gold quality
apex of heart	UBERON:0002098	88.89	gold quality
ectocervix	UBERON:0012249	88.82	gold quality
adipose tissue	UBERON:0001013	88.70	gold quality
left ovary	UBERON:0002119	88.60	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.49	gold quality
sural nerve	UBERON:0015488	88.04	gold quality
left uterine tube	UBERON:0001303	88.02	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	27.43
E-ANND-3	yes	12.78
E-CURD-114	no	51.02
E-GEOD-124858	no	50.75
E-MTAB-6379	no	2.90

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
CEL
IGFBP6	Repression
MYCN	Repression
NANOG	Repression
NEUROG1	Repression
NR5A2	Repression
ZIC5	Activation

JASPAR motifs

Motif	Name	Family
MA1421.1	TCF7L1	TCF-7-related factors

JASPAR matrix evidence (PMIDs): PMID:27447672

miRNA regulators (miRDB)

74 targeting TCF7L1, 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-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
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-6809-3P	99.91	71.45	3814
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AC	99.84	70.77	4351

Literature-anchored findings (GeneRIF, showing 21)

• No difference in nuclear beta-catenin signal intensity was found, which may be caused by an alteration in Wnt pathway in microsatellite stable sporadic tumors by unknown mechanisms leading to lower TCF-3, 4 protein expression. (PMID:20532534)
• HIPK2 up-regulates transcription by phosphorylating TCF3, a transcriptional repressor, but inhibits transcription by phosphorylating LEF1, a transcriptional activator. (PMID:21285352)
• Data indicate that median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >/=30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. (PMID:22930747)
• Tcf3is partially responsible for the butyrate-resistant phenotype of colorectal cancer cells, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. (PMID:23063976)
• Our results identify TCF3 as a central regulator of tumor growth and initiation. (PMID:23090119)
• TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments. (PMID:23492770)
• TCF/TLE tetramer complex promotes structural transitions of chromatin to mediate repression. (PMID:24596249)
• These results indicate that a dynamic interplay of TCF transcription factors governs MYC gene expression in colorectal cancers. (PMID:25659031)
• report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects (PMID:26764381)
• TCF7L1, a Wnt pathway repressor, buffers CTNNB1/TCF target gene expression to promote CRC growth (PMID:27333864)
• Through transcriptome profiling and combined gain- and loss-of-function studies, the authors identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. (PMID:28467300)
• TCF7L1 plays a major role in maintaining hESC pluripotency, which has implications for human development during gastrulation (PMID:29361574)
• Data indicate that transcription factor transcription factor 7-like 1 (TCF7L1) could regulate antioxidant response in gastric cancer cells by regulating Keap1/NRF2 [Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2] pathway. (PMID:30811526)
• Results provide some new insights into how extracellular signals modulate the self-renewal of liver CSCs and highlight the inhibitory roles of Tcf7l1 in cancer. (PMID:31322782)
• High TCF7L1 expression is associated with non-seminomatous testicular germ cell tumors. (PMID:31381875)
• Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies. (PMID:32403323)
• TCF7L1 Genetic Variants Are Associated with the Susceptibility to Cervical Cancer in a Chinese Population. (PMID:33824876)
• [T cell factor 3 (TCF3) is overexpressed in hepatocellular carcinoma and promotes their invasion and metastasis]. (PMID:35078577)
• TCF7L1 Regulates LGR5 Expression in Colorectal Cancer Cells. (PMID:36833408)
• MicroRNA-329-3p inhibits the Wnt/beta-catenin pathway and proliferation of osteosarcoma cells by targeting transcription factor 7-like 1. (PMID:38370338)
• TCF7L1 regulates colorectal cancer cell migration by repressing GAS1 expression. (PMID:38816533)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcf7l1b	ENSDARG00000007369
danio_rerio	tcf7l1a	ENSDARG00000038159
mus_musculus	Tcf7l1	ENSMUSG00000055799
rattus_norvegicus	Tcf7l1	ENSRNOG00000014753

Paralogs (3): TCF7 (ENSG00000081059), LEF1 (ENSG00000138795), TCF7L2 (ENSG00000148737)

Protein

Protein identifiers

Transcription factor 7-like 1 — Q9HCS4 (reviewed: Q9HCS4)

Alternative names: HMG box transcription factor 3

All UniProt accessions (2): Q9HCS4, C9JPE3

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the Wnt signaling pathway. Binds to DNA and acts as a repressor in the absence of CTNNB1, and as an activator in its presence. Necessary for the terminal differentiation of epidermal cells, the formation of keratohyalin granules and the development of the barrier function of the epidermis. Down-regulates NQO1, leading to increased mitomycin c resistance.

Subunit / interactions. Binds the armadillo repeat of CTNNB1 and forms a stable complex. Interacts with DAZAP2.

Subcellular location. Nucleus.

Tissue specificity. Detected in hair follicles and skin keratinocytes, and at lower levels in stomach epithelium.

Domain organisation. The putative Groucho interaction domain between the N-terminal CTNNB1 binding domain and the HMG-box is necessary for repression of the transactivation mediated by TCF7L1 and CTNNB1.

Similarity. Belongs to the TCF/LEF family.

RefSeq proteins (1): NP_112573* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR013558	CTNNB1-bd_N	Domain
IPR024940	TCF/LEF	Family
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR036910	HMG_box_dom_sf	Homologous_superfamily

Pfam: PF00505, PF08347

UniProt features (15 total): compositionally biased region 5, region of interest 4, sequence variant 2, chain 1, DNA-binding region 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCS4-F1	52.59	0.10

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-4086398	Ca2+ pathway
R-HSA-4411364	Binding of TCF/LEF:CTNNB1 to target gene promoters
R-HSA-4641265	Repression of WNT target genes
R-HSA-8951430	RUNX3 regulates WNT signaling
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-9834899	Specification of the neural plate border
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9758941	Gastrulation
R-HSA-9856651	MITF-M-dependent gene expression

MSigDB gene sets: 673 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, NIKOLSKY_OVERCONNECTED_IN_BREAST_CANCER, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_B_CELL_PROLIFERATION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (6): chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), regulation of Wnt signaling pathway (GO:0030111), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway (GO:0016055)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), beta-catenin-TCF complex (GO:1990907)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by WNT	3
TCF dependent signaling in response to WNT	2
Beta-catenin independent WNT signaling	1
Formation of the beta-catenin:TCF transactivating complex	1
Degradation of beta-catenin by the destruction complex	1
Transcriptional regulation by RUNX3	1
MITF-M-dependent gene expression	1
Gastrulation	1
Regulation of PD-L1(CD274) expression	1
Signal Transduction	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of DNA-templated transcription	2
Wnt signaling pathway	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular component organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
regulation of signal transduction	1
cell surface receptor signaling pathway	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

1610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCF7L1	CTNNB1	P35222	964
TCF7L1	HNF4A	P41235	767
TCF7L1	AXIN2	Q9Y2T1	721
TCF7L1	CTBP1	Q13363	713
TCF7L1	NAV2	Q8IVL1	674
TCF7L1	TCF7L2	Q9NQB0	628
TCF7L1	TERT	O14746	590
TCF7L1	BCL9	O00512	589
TCF7L1	MYC	P01106	585
TCF7L1	TCF3	P15883	580
TCF7L1	FZD5	Q13467	578
TCF7L1	CCND1	P24385	567
TCF7L1	TP53	P04637	556
TCF7L1	NANOG	Q9H9S0	543
TCF7L1	CTBP2	P56545	540

IntAct

4 interactions, top by confidence:

A	B	Type	Score
IFNA4	TCF7L1	psi-mi:“MI:0915”(physical association)	0.370
CTNNB1	TCF7L1	psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): TCF7L1 (Protein-peptide), TCF7L1 (Affinity Capture-MS), TCF7L1 (Affinity Capture-MS), TCF7L1 (Affinity Capture-Western), TCF7L1 (Affinity Capture-MS), TCF7L1 (Affinity Capture-MS), TCF7L1 (Co-crystal Structure), TCF7L1 (Affinity Capture-MS), TCF7L1 (Co-localization), TCF7L1 (Proximity Label-MS), TCF7L1 (Proximity Label-MS), TCF7L1 (Proximity Label-MS), TCF7L1 (Proximity Label-MS), TCF7L1 (Co-fractionation), TCF7L1 (Co-fractionation)

ESM2 similar proteins: A0JC51, A5ABV9, O08656, O09100, O18896, O57311, O60481, O73689, O95409, P09022, P10070, P19544, P22561, P23769, P23770, P23771, P23772, P23824, P25932, P46684, P49639, P49952, P54655, P55878, P70062, P70063, Q08DV0, Q0VGT2, Q15915, Q62520, Q62521, Q6DJQ6, Q6VVD7, Q6XP49, Q7TQ40, Q800Q5, Q8JJC0, Q91689, Q924A0, Q924Y4

Diamond homologs: A0A0G2JTZ2, A2TED3, A8WWH5, B1H349, B3DM43, O94993, O95416, P27782, P35711, P35712, P36389, P36390, P36393, P36394, P36396, P36402, P40645, P40647, P40656, P57073, P57074, P61259, P70062, P70063, P70064, P91943, Q00417, Q03256, Q04886, Q04892, Q05738, Q10666, Q28447, Q2PG84, Q32PP9, Q5RCU4, Q62563, Q62565, Q67EX7, Q69FB1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TCF7L1	“down-regulates quantity by repression”	NANOG	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1323 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	13
Uncertain significance	649
Likely benign	504
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1405740	NM_003200.5(TCF3):c.1331dup (p.Gly445fs)	Pathogenic
1450388	NM_003200.5(TCF3):c.1459C>T (p.Arg487Ter)	Pathogenic
1454718	NM_003200.5(TCF3):c.136G>T (p.Gly46Ter)	Pathogenic
1676601	NM_003200.5(TCF3):c.808C>T (p.Gln270Ter)	Pathogenic
1676602	TCF3, EX5-11 DEL	Pathogenic
2020729	NM_003200.5(TCF3):c.1169_1170insAA (p.Ser391fs)	Pathogenic
2029431	NM_003200.5(TCF3):c.310G>T (p.Glu104Ter)	Pathogenic
2073832	NM_003200.5(TCF3):c.670del (p.Ser224fs)	Pathogenic
225870	NM_001136139.4(TCF3):c.1663G>A (p.Glu555Lys)	Pathogenic
2420906	NM_003200.5(TCF3):c.961C>T (p.Arg321Ter)	Pathogenic
2422486	NC_000019.9:g.(?1206913)(1650247_?)del	Pathogenic
2700730	NM_003200.5(TCF3):c.1178_1181del (p.Ile393fs)	Pathogenic
2715547	NM_003200.5(TCF3):c.759_760del (p.Ser253fs)	Pathogenic
2859583	NM_003200.5(TCF3):c.1359dup (p.Gly454fs)	Pathogenic
2869183	NM_003200.5(TCF3):c.692dup (p.Gln233fs)	Pathogenic
3359020	NM_003200.5(TCF3):c.1913C>G (p.Ser638Ter)	Pathogenic
3377280	NM_003200.5(TCF3):c.604del (p.Ser202fs)	Pathogenic
3778414	NM_003200.5(TCF3):c.1081C>T (p.Gln361Ter)	Pathogenic
4774069	NM_003200.5(TCF3):c.1573dup (p.Arg525fs)	Pathogenic
4798196	NM_003200.5(TCF3):c.295G>T (p.Gly99Ter)	Pathogenic
4810505	NM_003200.5(TCF3):c.130C>T (p.Gln44Ter)	Pathogenic
982676	NM_003200.5(TCF3):c.1338_1360del (p.Ser446fs)	Pathogenic
2018154	NM_003200.5(TCF3):c.367-1G>T	Likely pathogenic
2029712	NM_003200.5(TCF3):c.1094-2A>T	Likely pathogenic
2129140	NM_003200.5(TCF3):c.550-1G>C	Likely pathogenic
2184750	NM_003200.5(TCF3):c.219+1G>C	Likely pathogenic
2799628	NM_003200.5(TCF3):c.1168-2A>G	Likely pathogenic
3255617	NM_001136139.4(TCF3):c.1643_1649dup (p.Asn551fs)	Likely pathogenic
3662484	NM_003200.5(TCF3):c.653-2A>G	Likely pathogenic
3728233	NM_003200.5(TCF3):c.1167+1G>A	Likely pathogenic

SpliceAI

3469 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85133930:GGAG:G	donor_gain	1.0000
2:85133931:G:GT	donor_gain	1.0000
2:85133931:GAG:G	donor_gain	1.0000
2:85133932:AGG:A	donor_loss	1.0000
2:85133933:GGTA:G	donor_loss	1.0000
2:85133934:G:GG	donor_gain	1.0000
2:85133934:GTAA:G	donor_loss	1.0000
2:85133939:G:GT	donor_gain	1.0000
2:85134010:CCGCA:C	acceptor_loss	1.0000
2:85134011:CGCA:C	acceptor_loss	1.0000
2:85134013:CA:C	acceptor_loss	1.0000
2:85134014:A:AG	acceptor_gain	1.0000
2:85134014:AGGC:A	acceptor_gain	1.0000
2:85134015:G:GG	acceptor_gain	1.0000
2:85134015:GGCG:G	acceptor_gain	1.0000
2:85134076:GAAG:G	donor_gain	1.0000
2:85134080:G:GA	donor_loss	1.0000
2:85134080:G:GG	donor_gain	1.0000
2:85134081:T:A	donor_loss	1.0000
2:85134446:GCACC:G	donor_gain	1.0000
2:85134451:G:GG	donor_gain	1.0000
2:85283481:T:TA	acceptor_gain	1.0000
2:85283488:T:A	acceptor_gain	1.0000
2:85283490:T:TA	acceptor_gain	1.0000
2:85283493:A:AG	acceptor_gain	1.0000
2:85283494:G:GT	acceptor_gain	1.0000
2:85283494:GT:G	acceptor_gain	1.0000
2:85283494:GTA:G	acceptor_gain	1.0000
2:85283494:GTAC:G	acceptor_gain	1.0000
2:85283494:GTACC:G	acceptor_gain	1.0000

AlphaMissense

3784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85306257:G:C	K347N	1.000
2:85306257:G:T	K347N	1.000
2:85306258:A:G	K348E	1.000
2:85306260:G:C	K348N	1.000
2:85306260:G:T	K348N	1.000
2:85306261:C:A	P349T	1.000
2:85306261:C:T	P349S	1.000
2:85306262:C:A	P349H	1.000
2:85306262:C:G	P349R	1.000
2:85306262:C:T	P349L	1.000
2:85306265:T:C	L350P	1.000
2:85306267:A:G	N351D	1.000
2:85306268:A:T	N351I	1.000
2:85306269:T:A	N351K	1.000
2:85306269:T:G	N351K	1.000
2:85306271:C:A	A352D	1.000
2:85306273:T:A	F353I	1.000
2:85306273:T:C	F353L	1.000
2:85306273:T:G	F353V	1.000
2:85306274:T:C	F353S	1.000
2:85306274:T:G	F353C	1.000
2:85306275:C:A	F353L	1.000
2:85306275:C:G	F353L	1.000
2:85306277:T:A	M354K	1.000
2:85306277:T:C	M354T	1.000
2:85306277:T:G	M354R	1.000
2:85306278:G:A	M354I	1.000
2:85306278:G:C	M354I	1.000
2:85306278:G:T	M354I	1.000
2:85306280:T:C	L355S	1.000

dbSNP variants (sampled 300 via entrez): RS1000020369 (2:85301505 A>C), RS1000048452 (2:85296051 C>G,T), RS1000057001 (2:85285733 C>G,T), RS1000072745 (2:85219421 C>T), RS1000076882 (2:85198343 A>G), RS1000078398 (2:85201988 G>A), RS1000078511 (2:85255359 A>C,G,T), RS1000085695 (2:85178283 T>C), RS1000104653 (2:85280379 C>T), RS1000157813 (2:85241131 A>G), RS1000167681 (2:85238950 G>C,T), RS1000171019 (2:85196901 C>T), RS1000183577 (2:85257788 G>A,T), RS1000209274 (2:85210813 G>A), RS1000211432 (2:85278876 G>A,T)

Disease associations

OMIM: gene MIM:604652 | disease phenotypes: MIM:616941, MIM:619824, MIM:300352, MIM:618718, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
agammaglobulinemia 8, autosomal dominant	Strong	Autosomal dominant
agammaglobulinemia 8b, autosomal recessive	Moderate	Autosomal recessive
autosomal agammaglobulinemia	Supportive	Autosomal dominant
combined pituitary hormone deficiencies, genetic form	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal agammaglobulinemia	Definitive	SD

Mondo (9): agammaglobulinemia 8, autosomal dominant (MONDO:0014840), agammaglobulinemia 8b, autosomal recessive (MONDO:0859234), myeloproliferative neoplasm, unclassifiable (MONDO:0019452), cerebral creatine deficiency syndrome (MONDO:0000456), neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia (MONDO:0032878), Castleman-Kojima disease (MONDO:0018702), plasma cell myeloma (MONDO:0009693), autosomal agammaglobulinemia (MONDO:0011096), combined pituitary hormone deficiencies, genetic form (MONDO:0013099)

Orphanet (5): Chronic myeloproliferative disease, unclassifiable (Orphanet:86830), Creatine deficiency syndrome (Orphanet:79172), TAFRO syndrome (Orphanet:457077), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002480_7	Hodgkin’s lymphoma	4.000000e-10
GCST003159_3	Objective response to lithium treatment	1.000000e-07
GCST004278_40	Pulse pressure	2.000000e-08
GCST005209_5	Hodgkin’s lymphoma	9.000000e-06
GCST005348_134	Total body bone mineral density	1.000000e-08
GCST006979_14	Heel bone mineral density	5.000000e-13
GCST007096_34	Pulse pressure	2.000000e-12
GCST007097_53	Pulse pressure	5.000000e-07
GCST007269_72	Pulse pressure	3.000000e-13
GCST007448_11	Normal facial asymmetry (angle of surface orientation score)	1.000000e-08
GCST007705_40	Pulse pressure	5.000000e-07
GCST007705_62	Pulse pressure	9.000000e-07
GCST012048_19	Triglyceride levels	8.000000e-07
GCST012490_194	Femur bone mineral density x serum urate levels interaction	9.000000e-10
GCST90002393_628	Monocyte count	5.000000e-09
GCST90002401_378	Platelet distribution width	4.000000e-09
GCST90011899_48	Aspartate aminotransferase levels	1.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0009270	heel bone mineral density
EFO:0009751	facial asymmetry measurement
EFO:0004530	triglyceride measurement
EFO:0004531	urate measurement
EFO:0005091	monocyte count
EFO:0007984	platelet component distribution width
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
C538056	Agammaglobulinemia, non-Bruton type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
entinostat	increases expression, affects cotreatment	2
bisphenol S	increases methylation, affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, increases expression	2
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
arsenite	affects binding, decreases reaction	1
sulforaphane	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
S 1 (combination)	decreases response to substance	1
penconazole	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
MRK 003	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8C4	Ubigene A-549 TCF7L1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study
NCT05722405	PHASE4	RECRUITING	Ixazomib Plus Low-dose Lenalidomide Versus Ixazomib Alone for Maintenance Treatment of High Risk Multiple Myeloma
NCT05855122	PHASE4	UNKNOWN	Safety and ASCT-related Symptom Burden Optimization of Tocilizumab in ASCT Following HD Melphalan Conditioning for Multiple Myeloma Patients
NCT05944783	PHASE4	NOT_YET_RECRUITING	Bioequivalence Studies of Dasatinib 100 Mg
NCT06057402	PHASE4	RECRUITING	Elranatamab Post Trial Access Study for Participants With Multiple Myeloma (MM)
NCT06251076	PHASE4	RECRUITING	Plan Development for Giving Teclistamab in the Outpatient Setting