AFF1

Summary

AFF1 (ALF transcription elongation factor 1, HGNC:7135) is a protein-coding gene on chromosome 4q21.3-q22.1, encoding AF4/FMR2 family member 1 (P51825).

This gene encodes a member of the AF4/ lymphoid nuclear protein related to the Fragile X E syndrome (FRAXE) family of proteins, which have been implicated in human childhood lymphoblastic leukemia, fragile chromosome X intellectual disability, and ataxia. It is the prevalent mixed-lineage leukemia fusion gene associated with spontaneous acute lymphoblastic leukemia. Members of this family have three conserved domains: an N-terminal homology domain, an AF4/ lymphoid nuclear protein domain, and a C-terminal homology domain. The protein functions as a regulator of RNA polymerase II-mediated transcription through elongation and chromatin remodeling functions. Through RNA interference screens, this gene has been shown to promote the expression of CD133, a plasma membrane glycoprotein required for leukemia cell survival. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4299 — RefSeq curated summary.

At a glance

• GWAS associations: 79
• Clinical variants (ClinVar): 251 total — 3 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001166693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7135
Approved symbol	AFF1
Name	ALF transcription elongation factor 1
Location	4q21.3-q22.1
Locus type	gene with protein product
Status	Approved
Aliases	AF-4, AF4, FEL
Ensembl gene	ENSG00000172493
Ensembl biotype	protein_coding
OMIM	159557
Entrez	4299

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000307808, ENST00000395146, ENST00000503369, ENST00000503477, ENST00000504956, ENST00000507468, ENST00000511442, ENST00000511722, ENST00000511996, ENST00000514970, ENST00000544085, ENST00000674009, ENST00000863512, ENST00000935002, ENST00000935003

RefSeq mRNA: 4 — MANE Select: NM_001166693 NM_001166693, NM_001313959, NM_001313960, NM_005935

CCDS: CCDS3616, CCDS54775, CCDS93557

Canonical transcript exons

ENST00000395146 — 21 exons

Exon	Start	End
ENSE00001196706	87114367	87115299
ENSE00001196711	87108159	87108315
ENSE00001196715	87105808	87105845
ENSE00001196725	87094915	87094969
ENSE00001196733	87091793	87091829
ENSE00001702244	86935011	86935240
ENSE00002430791	87132271	87132408
ENSE00002433077	87046695	87047594
ENSE00002445958	87127643	87127703
ENSE00002447098	87135580	87141039
ENSE00002448423	87126099	87126336
ENSE00002454493	87134471	87134694
ENSE00002472744	87131083	87131219
ENSE00002477603	87131793	87131864
ENSE00002500983	87127026	87127117
ENSE00002727782	87125037	87125143
ENSE00003500104	87046166	87046286
ENSE00003573706	86948498	86948571
ENSE00003671139	87089984	87090070
ENSE00003753824	87084120	87084164
ENSE00003787037	87105628	87105682

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.4759 / max 803.3682, expressed in 1817 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48685	14.5698	1781
48706	8.7067	1688
48686	8.2851	1693
48705	5.0372	1567
48701	3.4724	1308
48689	2.0817	693
48688	1.4540	650
48717	1.0462	625
48690	1.0412	461
48702	0.9247	474

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	99.27	gold quality
renal medulla	UBERON:0000362	99.13	gold quality
skin of hip	UBERON:0001554	98.75	gold quality
pigmented layer of retina	UBERON:0001782	98.63	gold quality
retina	UBERON:0000966	98.61	gold quality
cauda epididymis	UBERON:0004360	98.58	gold quality
trabecular bone tissue	UBERON:0002483	98.48	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.45	gold quality
seminal vesicle	UBERON:0000998	98.37	gold quality
caput epididymis	UBERON:0004358	98.37	gold quality
biceps brachii	UBERON:0001507	98.28	gold quality
gluteal muscle	UBERON:0002000	98.27	gold quality
germinal epithelium of ovary	UBERON:0001304	98.19	gold quality
vastus lateralis	UBERON:0001379	98.10	gold quality
superficial temporal artery	UBERON:0001614	98.09	gold quality
deltoid	UBERON:0001476	98.05	gold quality
quadriceps femoris	UBERON:0001377	98.03	gold quality
parietal pleura	UBERON:0002400	98.01	gold quality
mammary duct	UBERON:0001765	98.00	gold quality
body of tongue	UBERON:0011876	97.98	gold quality
colonic epithelium	UBERON:0000397	97.96	gold quality
pericardium	UBERON:0002407	97.90	gold quality
lower lobe of lung	UBERON:0008949	97.88	gold quality
tibialis anterior	UBERON:0001385	97.87	gold quality
corpus epididymis	UBERON:0004359	97.87	gold quality
pleura	UBERON:0000977	97.83	gold quality
cardia of stomach	UBERON:0001162	97.81	gold quality
pylorus	UBERON:0001166	97.80	gold quality
skeletal muscle tissue	UBERON:0001134	97.74	gold quality
epithelium of mammary gland	UBERON:0003244	97.74	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	25.80
E-MTAB-6058	no	999.30
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT2A

miRNA regulators (miRDB)

207 targeting AFF1, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548AE-3P	99.93	72.66	4867

Literature-anchored findings (GeneRIF, showing 40)

• lack of HOX gene expression in acute lymphoblastic leukemia B-cells was not due to a nonfunctional MLL/AF4 (PMID:14562113)
• the cell cycle control exerted by MLL-AF4 may be responsible of resistance to cell-death promoting stimuli in leukemia carrying the t(4;11) translocation. (PMID:14990976)
• role of interaction with SIAH1 and SIAH2 proteins in t(4,11) pathobiology (PMID:15221006)
• MLL-AF4 inhibits or activates CDKN1B expression. (PMID:16169901)
• The patients with immunophenotype of Pre-B-acute lymphoblastic leukemia were found to carry: MLL/AF4. (PMID:16215946)
• The TCR gene rearrangements in childhood B-lineage acute lymphoblastic leukemia was associated with expression of AF4 chimeric oncogene. (PMID:16386788)
• determination of the relative positions of MLL, AF4 and ENL genes, in two lymphoblastic and two myeloid human cell lines (PMID:16433901)
• The early onset of distinct mixed lymphoid/myeloid lineage deregulation in Mll-AF4 knock-in mice shows evidence for both “instructive” and “noninstructive” roles for AF4 and AF9 as partners in MLL fusion genes. (PMID:16551973)
• presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia (PMID:17130830)
• Gene rearrangement and genetic translocations observed in acute lymphoblastic leukemia. (PMID:17301807)
• demonstrate coimmunoprecipitation of the All1/Af4 and All1/Af9 fusions with Drosha, disrupted by treatment with DNase I (PMID:17581865)
• analysis of a rare MLL-AF4 (MLL-AFF1) fusion rearrangement in infant leukemia (PMID:17889710)
• Conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic and acute myeloid leukemias (PMID:18977325)
• findings suggest that the AF4-MLL protein disturbs the fine-tuned activation cycle of promoter-arrested RNA Pol II and causes altered histone methylation signatures (PMID:21030982)
• MLL-AF4 leukemogenesis has been particularly difficult to model and bona fide MLL-AF4 disease models do not exist so far.[review] (PMID:21135858)
• miR-143 functions as a tumor suppressor in MLL-AF4 B-cell acute lymphoblastic leukemia. (PMID:21706045)
• we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with Systemic lupus erythematosus susceptibility (rs340630; P = 8.3x10(-9), odds ratio = 1.21 (PMID:22291604)
• our findings show AF4-dependent regulation of CD133 expression, which is required for the growth of acute lymphoblastic leukemia cells (PMID:22337994)
• No association between AFF1 rs340630 and systemic lupus erythmatosus was found. (PMID:22983539)
• The structure of AF9 in complex with elongation factor AF4 reveals that aliphatic residues form an integral part of the hydrophobic core of the complex. (PMID:23260655)
• The FLT3-mediated inhibition of hematopoiesis in MLL-AF4-expressing human embryonic stem cells is associated with large transcriptional changes and downregulation of genes involved in hematopoietic system development and function. (PMID:23479570)
• Report generation of MLL/AF4 transgenic mice with the phenotype of lymphoblastic leukemia or lymphoma. (PMID:24189350)
• AFF1 is a ubiquitous P-TEFb partner; full Tat transactivation requires the complete super elongation complexes (PMID:24367103)
• AF4 and AF4-MLL mediate transcriptional elongation of 5-lipoxygenase mRNA by 1, 25-dihydroxyvitamin D3. (PMID:26329759)
• AF4 bindsto SL1 to initiate MLL fusion- and AEP-dependent transcription. (PMID:26593443)
• Presence of fusion the genes BCR/ABL1, ETV6/RUNX1, and MLL/AF4 does not have any impact on the clinical and laboratory features of ALL at presentation. (PMID:26856288)
• There was no association between AFF1 polymorphism (rs340630) and systemic lupus erythematosus. However, our findings indicated that AFF1 polymorphism (rs340630) was significantly (P=0.0045) correlated with renal disorder in Iranian population (PMID:27115110)
• Loss of MLL-AF4 activity results in a reduction of H3K79me3 levels in the gene body and H3K27Ac levels at the 3’ BCL-2 enhancer, revealing a novel regulatory link between these two histone marks and MLL-AF4-mediated activation of BCL-2. (PMID:27856324)
• MLL-AF4 fusion is associated with acute myeloid leukemia. (PMID:28114278)
• These results reveal a cooperative transcriptional activation mechanism of AEP and DOT1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia. (PMID:28394257)
• Our study represents the first report assessing the association of AFF1 rs340630 polymorphism with rheumatoid arthritis risk. No significant evidence was found for the dominant or recessive models. (PMID:29791587)
• we describe a functional and molecular cooperation between MA4 and A4M fusions during human hematopoietic development, and demonstrate how hESC-based hematopoietic differentiation represents a promising system to explore the developmental impact of the chimeric proteins resulting from chromosomal translocations, which remains obscure in human leukemia. (PMID:30679325)
• the scaffold protein 14-3-3theta; enhances the aberrant activity of the chimeric transcription factor MLL-AF4 and, therefore, represents a new player in the molecular pathogenesis of t(4;11)-positive leukemia (PMID:31493143)
• Osteopontin-c is overexpressed in KMT2A-AFF1 positive pediatric B-cell lymphoblastic leukemia when compared to those with ETV6-RUNX1"". (PMID:32114371)
• The data indicates that AFF1 inhibits adipogenic differentiation by regulating the transcription of TGM2. (PMID:32441391)
• HOXA9/IRX1 expression pattern defines two subgroups of infant MLL-AF4-driven acute lymphoblastic leukemia. (PMID:33069783)
• Suppression of the NTS-CPS1 regulatory axis by AFF1 in lung adenocarcinoma cells. (PMID:33493519)
• Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells. (PMID:33924850)
• Prognostic impact of KMT2A-AFF1-positivity in 926 BCR-ABL1-negative B-lineage acute lymphoblastic leukemia patients treated in GIMEMA clinical trials since 1996. (PMID:34048072)
• miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia. (PMID:34111240)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aff1	ENSMUSG00000029313
rattus_norvegicus	Aff1	ENSRNOG00000002232
drosophila_melanogaster	lilli	FBGN0041111

Paralogs (3): AFF4 (ENSG00000072364), AFF3 (ENSG00000144218), AFF2 (ENSG00000155966)

Protein

Protein identifiers

AF4/FMR2 family member 1 — P51825 (reviewed: P51825)

Alternative names: ALL1-fused gene from chromosome 4 protein, Protein FEL, Proto-oncogene AF4

All UniProt accessions (9): A0A669KBI3, D6RAU0, D6RIZ5, E7EMC5, E7ETI4, P51825, F5GXF9, H0Y9S4, Q14C88

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3).

Subcellular location. Nucleus.

Disease relevance. A chromosomal aberration involving AFF1 is associated with acute leukemias. Translocation t(4;11)(q21;q23) with KMT2A/MLL1. The result is a rogue activator protein.

Similarity. Belongs to the AF4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P51825-1	1	yes
P51825-2	2
P51825-3	3

RefSeq proteins (4): NP_001160165, NP_001300888, NP_001300889, NP_005926 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007797	AF4/FMR2	Family
IPR043639	AF4_int	Conserved_site
IPR043640	AF4/FMR2_CHD	Domain

Pfam: PF05110, PF18875, PF18876

UniProt features (46 total): compositionally biased region 19, modified residue 9, sequence conflict 8, region of interest 4, splice variant 2, sequence variant 2, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LM0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51825-F1	53.06	0.15

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 (9): 199, 206, 212, 220, 588, 681, 697, 750, 755

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 279 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, TATTATA_MIR374, HUMMERICH_BENIGN_SKIN_TUMOR_DN, HUMMERICH_MALIGNANT_SKIN_TUMOR_DN, FOSTER_TOLERANT_MACROPHAGE_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GROSS_HYPOXIA_VIA_ELK3_DN, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, RYTTCCTG_ETS2_B, JOSEPH_RESPONSE_TO_SODIUM_BUTYRATE_DN, TTTGCAC_MIR19A_MIR19B, GCM_DDX5, chr4q21

GO Biological Process (1): regulation of gene expression (GO:0010468)

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

GO Cellular Component (3): transcription elongation factor complex (GO:0008023), super elongation complex (GO:0032783), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gene expression	1
regulation of macromolecule biosynthetic process	1
binding	1
nucleoplasm	1
nuclear protein-containing complex	1
transcription elongation factor complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1933 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFF1	MLLT1	Q03111	999
AFF1	MLLT3	P42568	999
AFF1	ELL	P55199	998
AFF1	ELL2	O00472	997
AFF1	AFF4	Q9UHB7	985
AFF1	CCNT1	O60563	984
AFF1	MLLT10	P55197	979
AFF1	CDK9	P50750	979
AFF1	KMT2A	Q03164	978
AFF1	DOT1L	Q8TEK3	933
AFF1	ELL3	Q9HB65	928
AFF1	CCNT2	O60583	916
AFF1	CPZ	Q66K79	903
AFF1	EAF1	Q96JC9	871
AFF1	MLLT6	P55198	861

IntAct

77 interactions, top by confidence:

A	B	Type	Score
CDK9	CCNT1	psi-mi:“MI:0914”(association)	0.980
EAF1	ELL2	psi-mi:“MI:0914”(association)	0.840
AFF4	CCNT1	psi-mi:“MI:0914”(association)	0.810
MLLT3	AFF1	psi-mi:“MI:0407”(direct interaction)	0.730
MLLT3	AFF1	psi-mi:“MI:0915”(physical association)	0.730
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
AFF4	ELL2	psi-mi:“MI:0914”(association)	0.730
ELL3	CCNT1	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
MLLT1	ELL2	psi-mi:“MI:0914”(association)	0.640
tat	AHCYL1	psi-mi:“MI:0914”(association)	0.560
AFF1	tat	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (150): AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-MS), AFF1 (Affinity Capture-Western), AFF1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZM56, A2AG50, A2AI08, A2AJI0, A5D7K1, D4A4L4, E1C2Q8, F1LR10, O00515, O14529, O75128, O88573, O88735, P51825, P57016, Q14244, Q32LQ1, Q3KQU3, Q3U2K0, Q5JTD0, Q5NBX1, Q5PR69, Q5R7F9, Q5XHX2, Q5ZIA2, Q5ZJJ1, Q68DK7, Q6IPM2, Q6NV74, Q6NZF1, Q6PDH0, Q6PDM1, Q6PG95, Q6ZU35, Q86UU1, Q8CCJ4, Q8K124, Q8N7J2, Q8TD55, Q96PV7

Diamond homologs: B3MLB7, B3NAM7, B4JQ42, B4KFE1, B4LV24, B4MUE1, B4NXA8, O55112, P51816, P51825, P51826, P51827, Q29KG4, Q7YQM1, Q7YQM2, Q9ESC8, Q9UHB7, Q9VQI9, O88573

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AFF1	“form complex”	“AEP complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of RNA Pol II elongation complex	7	45.2×	1e-08
RNA Polymerase II Transcription Elongation	7	45.2×	1e-08
RNA Polymerase II Pre-transcription Events	7	32.1×	1e-07
RNA polymerase II transcribes snRNA genes	5	25.7×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
transcription elongation by RNA polymerase II	5	55.4×	4e-06
positive regulation of transcription elongation by RNA polymerase II	6	45.1×	1e-06

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — MEL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	187
Likely benign	20
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
147434	GRCh38/hg38 4q21.23-22.1(chr4:84329551-87679204)x1	Pathogenic
152920	GRCh38/hg38 4q21.23-21.3(chr4:85972086-87031375)x1	Pathogenic
3906911	GRCh37/hg19 4q21.23-22.1(chr4:84418529-88078532)x1	Pathogenic

SpliceAI

3941 predictions. Top by Δscore:

Variant	Effect	Δscore
4:87007421:CAAG:C	donor_loss	1.0000
4:87007424:GGTA:G	donor_loss	1.0000
4:87046142:A:AG	acceptor_gain	1.0000
4:87046149:T:A	acceptor_gain	1.0000
4:87046151:T:TA	acceptor_gain	1.0000
4:87046152:G:A	acceptor_gain	1.0000
4:87046155:A:AG	acceptor_gain	1.0000
4:87046155:ATCT:A	acceptor_gain	1.0000
4:87046158:T:TA	acceptor_gain	1.0000
4:87046163:CAGT:C	acceptor_loss	1.0000
4:87046164:A:AG	acceptor_gain	1.0000
4:87046165:G:GA	acceptor_gain	1.0000
4:87046282:ACAAG:A	donor_loss	1.0000
4:87046283:CAAG:C	donor_loss	1.0000
4:87046284:AAGG:A	donor_loss	1.0000
4:87046285:AGGT:A	donor_loss	1.0000
4:87046286:GGTA:G	donor_loss	1.0000
4:87046287:G:GC	donor_loss	1.0000
4:87046288:T:A	donor_loss	1.0000
4:87046691:TCAGA:T	acceptor_loss	1.0000
4:87046693:A:AG	acceptor_gain	1.0000
4:87046694:G:GG	acceptor_gain	1.0000
4:87046694:GA:G	acceptor_gain	1.0000
4:87046694:GAC:G	acceptor_gain	1.0000
4:87046694:GACA:G	acceptor_gain	1.0000
4:87084112:A:AG	acceptor_gain	1.0000
4:87084113:C:G	acceptor_gain	1.0000
4:87084119:GC:G	acceptor_gain	1.0000
4:87084119:GCA:G	acceptor_gain	1.0000
4:87084161:GAAG:G	donor_gain	1.0000

AlphaMissense

8016 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:87047437:T:A	V294D	0.999
4:87114391:T:A	W513R	0.999
4:87114391:T:C	W513R	0.999
4:87114393:G:C	W513C	0.999
4:87114393:G:T	W513C	0.999
4:87047433:T:C	Y293H	0.998
4:87047431:C:A	A292D	0.997
4:87047433:T:G	Y293D	0.996
4:87047439:C:G	R295G	0.996
4:87047437:T:C	V294A	0.995
4:87047443:C:A	P296H	0.995
4:87084157:T:C	I359T	0.995
4:87114406:T:A	W518R	0.995
4:87114406:T:C	W518R	0.995
4:87134667:G:C	A1162P	0.995
4:87047442:C:T	P296S	0.994
4:87084157:T:G	I359S	0.994
4:87089999:T:A	W367R	0.994
4:87089999:T:C	W367R	0.994
4:87114408:G:C	W518C	0.994
4:87114408:G:T	W518C	0.994
4:87047442:C:A	P296T	0.993
4:87084160:T:C	L360P	0.993
4:87089988:T:C	M363T	0.993
4:87047433:T:A	Y293N	0.992
4:87114392:G:C	W513S	0.992
4:87046216:G:C	R23P	0.991
4:87047443:C:G	P296R	0.991
4:87090012:T:C	L371S	0.991
4:87114398:T:A	L515Q	0.991

dbSNP variants (sampled 300 via entrez): RS1000027316 (4:87098196 G>A,T), RS1000028612 (4:87052166 G>A,C,T), RS1000029595 (4:87138146 C>T), RS1000043124 (4:87131604 A>G,T), RS1000043540 (4:87095812 T>C), RS1000044620 (4:87020407 A>T), RS1000082113 (4:86936184 G>A,T), RS1000087806 (4:87092008 G>A,T), RS1000102082 (4:86937358 C>T), RS1000108832 (4:87089678 T>A), RS1000126237 (4:86998571 A>C,G), RS1000141866 (4:87125562 G>A), RS1000167010 (4:87028796 T>C,G), RS1000184242 (4:86955854 G>A,C), RS1000185524 (4:86949012 A>G)

Disease associations

OMIM: gene MIM:159557 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): teratoma (MONDO:0002601)

Orphanet (0):

HPO phenotypes

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

GWAS associations

79 associations (top):

Study	Trait	p-value
GCST000758_28	Triglycerides	9.000000e-12
GCST000809_8	Triglycerides	3.000000e-10
GCST001384_1	Systemic lupus erythematosus	8.000000e-09
GCST001915_7	Alzheimer’s disease (cognitive decline)	2.000000e-07
GCST001958_16	Bulimia nervosa	4.000000e-06
GCST002897_28	Triglycerides	2.000000e-10
GCST003476_4	Eyebrow thickness	2.000000e-06
GCST004599_89	Mean platelet volume	6.000000e-10
GCST004601_59	Red blood cell count	1.000000e-11
GCST004602_152	Mean corpuscular volume	2.000000e-15
GCST004604_95	Hematocrit	3.000000e-16
GCST004615_18	Hemoglobin concentration	1.000000e-17
GCST004618_63	White blood cell count (basophil)	1.000000e-24
GCST004630_141	Mean corpuscular hemoglobin	9.000000e-15
GCST004631_64	Basophil percentage of white cells	1.000000e-24
GCST004631_65	Basophil percentage of white cells	4.000000e-27
GCST004634_25	Basophil percentage of granulocytes	6.000000e-26
GCST005976_16	White blood cell count (basophil)	1.000000e-08
GCST005980_16	Total bilirubin levels	4.000000e-08
GCST005993_75	Mean corpuscular hemoglobin	8.000000e-09
GCST005994_21	Hematocrit	8.000000e-13
GCST005995_9	Hemoglobin	2.000000e-11
GCST006011_106	Mean corpuscular volume	1.000000e-09
GCST006288_313	Heel bone mineral density	9.000000e-07
GCST006288_524	Heel bone mineral density	1.000000e-09
GCST006613_47	Triglycerides	8.000000e-28
GCST006979_439	Heel bone mineral density	8.000000e-40
GCST007828_2	Diastolic blood pressure	3.000000e-07
GCST007932_51	Medication use (thyroid preparations)	1.000000e-08
GCST008070_38	HDL cholesterol levels	9.000000e-09

EFO canonical traits (21, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0005090	basophil count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007992	basophil percentage of leukocytes
EFO:0007995	basophil percentage of granulocytes
EFO:0004570	bilirubin measurement
EFO:0009270	heel bone mineral density
EFO:0006945	diastolic blood pressure change measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0000195	metabolic syndrome
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004462	PR interval
EFO:0006925	lipoprotein A measurement
EFO:0004587	lymphocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013724	Teratoma	C04.557.465.910

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724736 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.89	Kd	13	nM	MOLIBRESIB
7.70	IC50	20	nM	MOLIBRESIB
5.89	Kd	1301	nM	CHEMBL5653589
5.85	ED50	1404	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 9 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179203: Binding affinity against AFF1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0130	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147813: Binding affinity to human AFF1 incubated for 45 mins by Kinobead based pull down assay	kd	1.3006	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	4
Arsenic	affects methylation, decreases methylation, increases expression	3
sodium arsenite	affects expression, increases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, increases methylation	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
coumarin	increases phosphorylation	1
cupric oxide	increases expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
dimethylthioarsinic acid	increases expression	1
Bortezomib	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650855	Binding	Binding affinity to human AFF1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

28 cell lines: 24 cancer cell line, 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0064	MV4-11	Cancer cell line	Male
CVCL_0081	BEL-1	Cancer cell line	Female
CVCL_0093	RS4;11	Cancer cell line	Female
CVCL_0095	SEM	Cancer cell line	Female
CVCL_1069	ALL-PO	Cancer cell line	Female
CVCL_3993	KOCL-45	Cancer cell line	Male
CVCL_3994	KOCL-58	Cancer cell line	Male
CVCL_3995	KOCL-69	Cancer cell line	Female
CVCL_6867	KOCL-48	Cancer cell line	Female
CVCL_7125	SCMC-L1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00104676	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage II or Stage III Germ Cell Tumors
NCT02375204	PHASE3	ACTIVE_NOT_RECRUITING	Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ Cell Tumors
NCT00002931	PHASE2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Germ Cell Cancer
NCT00301782	PHASE2	COMPLETED	Combination Chemotherapy in Treating Male Patients With Germ Cell Tumors
NCT00432094	PHASE2	COMPLETED	Autologous Peripheral Blood Stem Cell Transplant for Germ Cell Tumors
NCT00453232	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Men With Metastatic Germ Cell Tumors
NCT00453310	PHASE2	COMPLETED	Sunitinib in Treating Patients With Metastatic Germ Cell Tumors That Have Relapsed or Not Responded to Treatment
NCT00470366	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Patients With Previously Untreated Germ Cell Tumors
NCT02300987	PHASE2	COMPLETED	A Randomized, Blinded, Placebo-controlled, Phase II Trial of LEE011 in Patients With Relapsed, Refractory, Incurable Teratoma With Recent Progression
NCT00003643	PHASE2/PHASE3	UNKNOWN	Combination Chemotherapy in Treating Men With Germ Cell Cancer
NCT00423852	PHASE1/PHASE2	COMPLETED	Paclitaxel, Ifosfamide, and Carboplatin Followed By Autologous Stem Cell Transplant in Treating Patients With Germ Cell Tumors That Did Not Respond to Cisplatin
NCT00687778	Not specified	UNKNOWN	11C-Acetate PET/CT Non-FDG-Avid Tumors
NCT00836121	Not specified	COMPLETED	Anterior Mediastinum Teratoma: A Case Report
NCT05179850	Not specified	UNKNOWN	Computer Aided Diagnostic Tool on Computed Tomography Images for Diagnosis of Retroperitoneal Tumor in Children
NCT05187923	Not specified	UNKNOWN	Computer Aided Tool for Diagnosis of Neck Masses in Children
NCT05564026	Not specified	RECRUITING	Molecular Epidemiology of Pediatric Germ Cell Tumors
NCT06421805	Not specified	RECRUITING	Establishing Prospective Mediastinal Tumor Database of PUMCH
NCT07199699	Not specified	NOT_YET_RECRUITING	Subxiphoid VATS for Giant Mediastinal Teratoma