FEM1B

Summary

FEM1B (fem-1 homolog B, HGNC:3649) is a protein-coding gene on chromosome 15q23, encoding Protein fem-1 homolog B (Q9UK73). Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation.

This gene encodes an ankyrin repeat protein that belongs to the death receptor-associated family of proteins and plays a role in mediating apoptosis. The encoded protein is also thought to function in the replication stress-induced checkpoint signaling pathway via interaction with checkpoint kinase 1.

Source: NCBI Gene 10116 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic disease (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 52 total — 1 pathogenic
• Phenotypes (HPO): 136
• Druggable target: yes
• MANE Select transcript: NM_015322

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3649
Approved symbol	FEM1B
Name	fem-1 homolog B
Location	15q23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000169018
Ensembl biotype	protein_coding
OMIM	613539
Entrez	10116

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000306917, ENST00000566008, ENST00000566739, ENST00000570067

RefSeq mRNA: 1 — MANE Select: NM_015322 NM_015322

CCDS: CCDS10228

Canonical transcript exons

ENST00000306917 — 2 exons

Exon	Start	End
ENSE00001197611	68289607	68295862
ENSE00001335298	68277745	68278665

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1166 / max 119.9135, expressed in 1813 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147386	12.5907	1792
147388	6.7060	1700
147387	1.0656	667
147385	0.3867	234
147389	0.2843	118
147395	0.0784	6
147394	0.0050	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.08	gold quality
left testis	UBERON:0004533	95.56	gold quality
right testis	UBERON:0004534	95.26	gold quality
adrenal tissue	UBERON:0018303	95.10	gold quality
cortical plate	UBERON:0005343	94.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.59	gold quality
testis	UBERON:0000473	94.24	gold quality
esophagus squamous epithelium	UBERON:0006920	94.11	gold quality
sperm	CL:0000019	94.01	gold quality
middle temporal gyrus	UBERON:0002771	93.98	gold quality
calcaneal tendon	UBERON:0003701	93.69	gold quality
amniotic fluid	UBERON:0000173	93.46	gold quality
male germ cell	CL:0000015	93.12	gold quality
tendon	UBERON:0000043	92.95	gold quality
medial globus pallidus	UBERON:0002477	92.95	gold quality
upper leg skin	UBERON:0004262	92.89	gold quality
globus pallidus	UBERON:0001875	92.22	gold quality
islet of Langerhans	UBERON:0000006	92.05	gold quality
descending thoracic aorta	UBERON:0002345	91.88	gold quality
parietal pleura	UBERON:0002400	91.87	gold quality
gastrocnemius	UBERON:0001388	91.79	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.68	gold quality
stromal cell of endometrium	CL:0002255	91.56	gold quality
thoracic aorta	UBERON:0001515	91.41	gold quality
squamous epithelium	UBERON:0006914	91.41	gold quality
ganglionic eminence	UBERON:0004023	91.32	gold quality
saphenous vein	UBERON:0007318	91.31	gold quality
ascending aorta	UBERON:0001496	91.30	gold quality
epithelium of esophagus	UBERON:0001976	91.30	gold quality
pleura	UBERON:0000977	91.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

212 targeting FEM1B, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 10)

• This study presents evidence suggesting a role for FEM1A and FEM1B in the pathogenesis of polycystic ovary syndrome. Only FEM1B variants were associated with insulin-related traits in PCOS women. (PMID:18757445)
• FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress. (PMID:19330022)
• the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells (PMID:19908242)
• These findings have implications for understanding the cellular functions of Fem1b, and the regulation of Gli1 oncoprotein activity. (PMID:24076122)
• FEM1 proteins are ancient regulators of Stem-Loop Binding Protein. (PMID:28118078)
• Molecular basis for arginine C-terminal degron recognition by Cul2(FEM1) E3 ligase. (PMID:33398168)
• Molecular basis for ubiquitin ligase CRL2(FEM1C)-mediated recognition of C-degron. (PMID:33398170)
• Structural insights into SMCR8 C-degron recognition by FEM1B. (PMID:33892462)
• Structural insights into the ubiquitylation strategy of the oligomeric CRL2[FEM1B] E3 ubiquitin ligase. (PMID:38360992)
• A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder. (PMID:38465576)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fem1b	ENSMUSG00000032244
rattus_norvegicus	Fem1b	ENSRNOG00000007077
drosophila_melanogaster	Fem-1	FBGN0034542
caenorhabditis_elegans		WBGENE00001411

Paralogs (4): FEM1A (ENSG00000141965), FEM1C (ENSG00000145780), ANKRD33B (ENSG00000164236), ANKRD33 (ENSG00000167612)

Protein

Protein identifiers

Protein fem-1 homolog B — Q9UK73 (reviewed: Q9UK73)

Alternative names: FEM1-beta, Fem-1-like death receptor-binding protein alpha, Fem-1-like in apoptotic pathway protein alpha

All UniProt accessions (3): Q9UK73, H3BT12, H3BTV3

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(FEM1B) complex specifically recognizes proteins ending with -Gly-Leu-Asp-Arg, such as CDK5R1, leading to their ubiquitination and degradation. Also acts as a regulator of the reductive stress response by mediating ubiquitination of reduced FNIP1: in response to reductive stress, the CRL2(FEM1B) complex specifically recognizes a conserved Cys degron in FNIP1 when this degron is reduced, leading to FNIP1 degradation and subsequent activation of mitochondria to recalibrate reactive oxygen species (ROS). Mechanistically, recognizes and binds reduced FNIP1 through two interface zinc ions, which act as a molecular glue that recruit reduced FNIP1 to FEM1B. Promotes ubiquitination of GLI1, suppressing GLI1 transcriptional activator activity. Promotes ubiquitination and degradation of ANKRD37. Promotes ubiquitination and degradation of SLBP. Involved in apoptosis by acting as a death receptor-associated protein that mediates apoptosis. Also involved in glucose homeostasis in pancreatic islet. May also act as an adapter/mediator in replication stress-induced signaling that leads to the activation of CHEK1.

Subunit / interactions. Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter FEM1B. Homooligomer. Interacts with PPM1F and PHTF1. Interacts with the death domain of FAS/TNFRSF6 and TNFRSF1A. Interacts with CHEK1. Interacts with NKX3-1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed. Highly expressed in testis. Weakly expressed in other tissues.

Disease relevance. Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities (NEDBES) [MIM:621263] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, and behavioral abnormalities. Additional variable features include brain anomalies, clubfeet, skeletal abnormalities, facial dysmorphism, dysplastic ears, and hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activity of the CRL2(FEM1B) complex toward FNIP1 is inhibited by BEX family proteins (BEX1, BEX2, BEX3, BEX4 and/or BEX5) in absence of reductive stress. Mechanistically, BEX proteins act as pseudosubstrate inhibitors that associate with FEM1B via zinc in absence of reductive stress, thereby preventing association between FEM1B and FNIP1.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the fem-1 family.

RefSeq proteins (1): NP_056137* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF12796

UniProt features (75 total): helix 36, repeat 9, strand 9, mutagenesis site 8, turn 6, binding site 4, chain 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

31 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9PW8	X-RAY DIFFRACTION	2.8
7EL6	X-RAY DIFFRACTION	2.8
9PQA	X-RAY DIFFRACTION	2.9
9PQ9	X-RAY DIFFRACTION	2.93
9PWJ	X-RAY DIFFRACTION	3
9PXP	X-RAY DIFFRACTION	3
9PXO	X-RAY DIFFRACTION	3.05
9PQE	X-RAY DIFFRACTION	3.1
6LBF	X-RAY DIFFRACTION	3.25
8WQF	ELECTRON MICROSCOPY	3.27
8WQB	ELECTRON MICROSCOPY	3.37
8WQE	ELECTRON MICROSCOPY	3.38
8WQA	ELECTRON MICROSCOPY	3.39
8WQH	ELECTRON MICROSCOPY	3.44
7CNG	X-RAY DIFFRACTION	3.49
8WQI	ELECTRON MICROSCOPY	3.5
8WQC	ELECTRON MICROSCOPY	3.54
8WQD	ELECTRON MICROSCOPY	3.55
9J77	ELECTRON MICROSCOPY	3.56
9JCE	ELECTRON MICROSCOPY	3.59
8JE2	ELECTRON MICROSCOPY	3.63
9LKX	ELECTRON MICROSCOPY	3.76
9J78	ELECTRON MICROSCOPY	3.88
9LKY	ELECTRON MICROSCOPY	3.93
8JE1	ELECTRON MICROSCOPY	3.95
9J79	ELECTRON MICROSCOPY	4.08
8WQG	ELECTRON MICROSCOPY	4.09
9J7B	ELECTRON MICROSCOPY	4.12
9J7A	ELECTRON MICROSCOPY	4.13
8IJ1	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK73-F1	94.46	0.84

Functional residue map

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

Catalytic / active sites (1): 342–343 (cleavage; by a caspase-3-like protease)

Ligand- & substrate-binding residues (4): 185; 186; 186; 218

Mutagenesis-validated functional residues (8):

Position	Phenotype
82	abolished binding to -gly-leu-asp-arg c-degron at the c-terminus; when associated with a-131.
130	abolished binding to -gly-leu-asp-arg c-degron at the c-terminus.
131	abolished binding to -gly-leu-asp-arg c-degron at the c-terminus; when associated with a-82.
163	strongly reduced binding to -gly-leu-asp-arg c-degron at the c-terminus; when associated with a-193.
193	strongly reduced binding to -gly-leu-asp-arg c-degron at the c-terminus; when associated with a-163.
342	prevents cleavage by a caspase-3-like protease.
356	does not affect cleavage by a caspase-3-like protease.
597	abolished ability to promote ubiquitination of target proteins such as gli1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 241 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_GLAND_MORPHOGENESIS, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_ANATOMICAL_STRUCTURE_MATURATION

GO Biological Process (10): apoptotic process (GO:0006915), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of ubiquitin-protein transferase activity (GO:0051438), branching involved in prostate gland morphogenesis (GO:0060442), epithelial cell maturation involved in prostate gland development (GO:0060743), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627), regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902041), regulation of DNA damage checkpoint (GO:2000001), epithelial cell maturation (GO:0002070)

GO Molecular Function (4): death receptor binding (GO:0005123), metal ion binding (GO:0046872), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (7): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), Cul2-RING ubiquitin ligase complex (GO:0031462)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
cytoplasm	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
ubiquitin-protein transferase activity	1
regulation of transferase activity	1
prostate gland morphogenesis	1
prostate gland epithelium morphogenesis	1
morphogenesis of a branching epithelium	1
epithelial cell maturation	1
prostate gland development	1
epithelial cell differentiation involved in prostate gland development	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
extrinsic apoptotic signaling pathway via death domain receptors	1
regulation of extrinsic apoptotic signaling pathway	1
DNA damage checkpoint signaling	1
regulation of cellular response to stress	1
regulation of cell cycle checkpoint	1
epithelial cell development	1
cell maturation	1
tumor necrosis factor receptor superfamily binding	1
cation binding	1
enzyme-substrate adaptor activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
nuclear lumen	1
intracellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1699 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FEM1B	CUL2	Q13617	726
FEM1B	ANKRD37	Q7Z713	698
FEM1B	CHEK1	O14757	654
FEM1B	LRR1	Q96L50	598
FEM1B	GLI1	P08151	558
FEM1B	RACK1	P25388	557
FEM1B	FAS	P25445	556
FEM1B	TNFRSF1A	P19438	521
FEM1B	RAD9A	Q99638	519
FEM1B	INTS6	Q9UL03	506
FEM1B	PPM1F	P49593	500
FEM1B	RAD17	O75943	494
FEM1B	CASZ1	Q86V15	492
FEM1B	PHTF1	Q9UMS5	482
FEM1B	LRRIQ1	Q96JM4	461

IntAct

153 interactions, top by confidence:

A	B	Type	Score
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
NEDD8	UBE2M	psi-mi:“MI:0914”(association)	0.940
COPS2	GPS1	psi-mi:“MI:0914”(association)	0.860
COPS8	COPS2	psi-mi:“MI:0914”(association)	0.850
SHKBP1	CUL3	psi-mi:“MI:0914”(association)	0.850
MAPK8IP1	MAPK8	psi-mi:“MI:0914”(association)	0.770
TOMM22	TOMM40	psi-mi:“MI:0914”(association)	0.740
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
CUL2	COPS2	psi-mi:“MI:0914”(association)	0.640
CUL5	SOCS7	psi-mi:“MI:0914”(association)	0.640
TOMM22	XRCC3	psi-mi:“MI:0914”(association)	0.640
SHKBP1	YWHAH	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
TRIM44	CUL2	psi-mi:“MI:0914”(association)	0.640
GLMN	CUL2	psi-mi:“MI:0914”(association)	0.640
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
HIF1AN	FEM1B	psi-mi:“MI:0210”(hydroxylation reaction)	0.590
HIF1AN	FEM1B	psi-mi:“MI:0915”(physical association)	0.590
FEM1B	PPM1F	psi-mi:“MI:0407”(direct interaction)	0.540
PPM1F	FEM1B	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (156): FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-Western), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS), FEM1B (Affinity Capture-MS)

ESM2 similar proteins: A6NK59, A7MB89, B4E2M5, P0C6P7, P0C927, Q08DV6, Q29RM5, Q3SX45, Q3SZE4, Q3UMR0, Q495B1, Q4V890, Q5R5S1, Q5REW9, Q5RFS1, Q5U2S6, Q5ZM55, Q6GPE5, Q7T3P8, Q810B6, Q8C0T1, Q8C6Y6, Q8CEF1, Q8CEL2, Q8HXA6, Q8K0L0, Q8N9B4, Q8VHS6, Q8WXH4, Q8WXK1, Q91ZT8, Q96DX5, Q96JP0, Q96NW4, Q96Q27, Q9BSK4, Q9CQ31, Q9GKW8, Q9H0C1, Q9P2R3

Diamond homologs: A1ZBY1, A7MB89, P0C6P7, Q29RM5, Q2T9K6, Q4V890, Q5ZM55, Q6GPE5, Q6P9Z4, Q7T3P8, Q8C0T1, Q8CEF1, Q96JP0, Q9BSK4, Q9UK73, Q9VFD5, Q9Z2G0, Q9Z2G1, P17221, Q66H07, Q6NLQ8, A2ARS0, C9JTQ0, Q55FM5, Q5ZLC8, O90760, Q09YI3, Q4UJC0, Q8WMX8, Q9FPH0, P25963, Q08353, O15084, Q337A0, Q3SX00, Q4FE45, Q4JHE0, Q505D1, Q5R8C8, Q65XV2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 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
DNA Damage Recognition in GG-NER	9	23.4×	4e-08
Formation of TC-NER Pre-Incision Complex	9	17.3×	4e-07
Cargo recognition for clathrin-mediated endocytosis	10	9.5×	1e-05
Neddylation	19	8.2×	8e-10

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	9	58.1×	5e-12
protein neddylation	11	53.3×	3e-14
intrinsic apoptotic signaling pathway	5	12.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4056368	NM_015322.5(FEM1B):c.377G>A (p.Arg126Gln)	Pathogenic

SpliceAI

931 predictions. Top by Δscore:

Variant	Effect	Δscore
15:68289604:TAGG:T	acceptor_loss	1.0000
15:68289605:AGGT:A	acceptor_loss	1.0000
15:68289606:G:A	acceptor_loss	1.0000
15:68289606:GGT:G	acceptor_gain	1.0000
15:68289606:GGTAT:G	acceptor_gain	1.0000
15:68291239:T:TG	donor_gain	1.0000
15:68278661:GACGG:G	donor_gain	0.9900
15:68278664:GG:G	donor_gain	0.9900
15:68278664:GGGTA:G	donor_loss	0.9900
15:68278665:GG:G	donor_gain	0.9900
15:68278666:G:GG	donor_gain	0.9900
15:68278666:GTA:G	donor_loss	0.9900
15:68278667:T:A	donor_loss	0.9900
15:68289600:T:G	acceptor_gain	0.9900
15:68291239:T:G	donor_gain	0.9900
15:68282476:A:G	acceptor_gain	0.9800
15:68289599:A:AG	acceptor_gain	0.9800
15:68289605:A:AG	acceptor_gain	0.9800
15:68289606:G:GG	acceptor_gain	0.9800
15:68289606:GGTA:G	acceptor_gain	0.9800
15:68278496:C:A	acceptor_gain	0.9700
15:68278599:T:TA	donor_gain	0.9700
15:68278600:G:GA	donor_gain	0.9700
15:68279103:G:GG	donor_gain	0.9700
15:68282475:AAAT:A	acceptor_gain	0.9700
15:68284837:GTAA:G	acceptor_gain	0.9700
15:68289599:ATGT:A	acceptor_gain	0.9700
15:68289605:AG:A	acceptor_gain	0.9700
15:68289606:GG:G	acceptor_gain	0.9700
15:68282475:A:AG	acceptor_gain	0.9600

AlphaMissense

4158 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:68278452:C:A	A12D	1.000
15:68278578:C:A	A54D	1.000
15:68278587:G:T	G57V	1.000
15:68278653:T:A	V79D	1.000
15:68289633:T:A	L92H	1.000
15:68289635:T:A	W93R	1.000
15:68289635:T:C	W93R	1.000
15:68289637:G:C	W93C	1.000
15:68289637:G:T	W93C	1.000
15:68289640:T:G	C94W	1.000
15:68289645:C:A	A96D	1.000
15:68289711:C:T	T118I	1.000
15:68289722:T:C	S122P	1.000
15:68289723:C:T	S122L	1.000
15:68289729:C:A	P124H	1.000
15:68289729:C:G	P124R	1.000
15:68289741:C:A	A128E	1.000
15:68289743:T:C	C129R	1.000
15:68289744:G:A	C129Y	1.000
15:68289745:C:G	C129W	1.000
15:68289746:T:C	F130L	1.000
15:68289748:T:A	F130L	1.000
15:68289748:T:G	F130L	1.000
15:68289777:T:C	L140S	1.000
15:68289777:T:G	L140W	1.000
15:68289810:A:T	N151I	1.000
15:68289811:C:A	N151K	1.000
15:68289811:C:G	N151K	1.000
15:68289823:C:A	N155K	1.000
15:68289823:C:G	N155K	1.000

dbSNP variants (sampled 300 via entrez): RS1000254905 (15:68294247 A>G), RS1000434228 (15:68275829 G>A), RS1000466750 (15:68276006 G>A,C), RS1000530405 (15:68288950 C>T), RS1000542422 (15:68282331 C>T), RS1000968046 (15:68279800 A>G), RS1000983905 (15:68286648 G>A), RS1001037755 (15:68286363 G>A), RS1001059982 (15:68277479 G>A,C), RS1001336573 (15:68279483 T>C), RS1001345247 (15:68277590 G>A,C), RS1001452062 (15:68278733 C>A), RS1001655859 (15:68289940 A>G), RS1001707957 (15:68289370 T>A), RS1001869358 (15:68283128 A>T)

Disease associations

OMIM: gene MIM:613539 | disease phenotypes: MIM:256730, MIM:621263

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (4): neuronal ceroid lipofuscinosis (MONDO:0016295), neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities (MONDO:0979245), complex neurodevelopmental disorder (MONDO:0100038), syndromic disease (MONDO:0002254)

Orphanet (2): Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263)

HPO phenotypes

136 total (30 of 136 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000074	Ureteropelvic junction obstruction
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000403	Recurrent otitis media
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000483	Astigmatism
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000579	Nasolacrimal duct obstruction
HP:0000646	Amblyopia
HP:0000664	Synophrys

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001850_6	Major depressive disorder	3.000000e-07
GCST003670_1	Systolic blood pressure	3.000000e-08
GCST90002383_227	Hematocrit	2.000000e-09
GCST90002384_390	Hemoglobin	7.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013577	Syndrome	C23.550.288.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (15): CHEMBL5291587 (SINGLE PROTEIN), CHEMBL5291963 (PROTEIN-PROTEIN INTERACTION), CHEMBL5291964 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195587 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195588 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195589 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195590 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195591 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195592 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195593 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	EC50	250	nM	CHEMBL5282395
5.82	IC50	1500	nM	CHEMBL5269604
5.66	IC50	2200	nM	CHEMBL5289726

PubChem BioAssay actives

4 with measured affinity, of 8 total; 3 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
N-[4-[[2-[7-[but-3-ynyl-(2-chloroacetyl)amino]-2,3-dihydro-1,4-benzoxazin-4-yl]acetyl]amino]butyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide	1946242: Protac activity at FEM1B/BRD4 in human HEK293T cells assessed as degradation of BRD4 incubated for 8 hrs by Western blot analysis	ec50	0.2500	uM
N-[5-[[2-[7-[(2-chloroacetyl)-(2-cyanoethyl)amino]-2,3-dihydro-1,4-benzoxazin-4-yl]acetyl]amino]pentyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide	1921391: Binding affinity to FEM1B (unknown origin)	ic50	1.5000	uM
2-chloro-N-(2-cyanoethyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide	1939926: Inhibition of FEMIB/FNIP1 interaction in human HEK293T cells	ic50	2.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
nickel chloride	decreases expression	1
cadmium sulfate	decreases expression	1
cordycepin	affects expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	increases expression	1
Doxorubicin	affects expression	1
Estradiol	affects expression	1
Formaldehyde	decreases expression	1
Lead	affects expression	1
Phenobarbital	affects expression	1
Plant Extracts	increases expression, affects cotreatment	1
Smoke	decreases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Valproic Acid	decreases methylation	1

ChEMBL screening assays

29 unique, capped per target: 29 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5224356	Binding	Binding affinity to FEM1B (unknown origin)	Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1R1	SEES3-1V human FEM1B, clone1	Embryonic stem cell	Male
CVCL_A1R2	SEES3-1V human FEM1B, clone2	Embryonic stem cell	Male
CVCL_A1R3	SEES3-1V human FEM1B, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00027456	PHASE2	COMPLETED	Leptin to Treat Severe Insulin Resistance - Pilot Study
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00213447	Not specified	COMPLETED	T Cell Response in Hypersensitivity Syndrome
NCT02240888	Not specified	COMPLETED	Vaccination in Inflammatory Rheumatic Disease (VACCIMIL). The Impact of Antirheumatic Treatment on Antibody Response
NCT02526082	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of the Helsinki Businessmen Study
NCT02637518	Not specified	UNKNOWN	Comprehensive Validation of Frailty Assessment Tools in Older Adults in Different Clinical and Social Settings
NCT02971072	Not specified	COMPLETED	Neurophysiology of Weakness and Exercise in Rotator Cuff Tendinopathy
NCT02974569	Not specified	COMPLETED	Improving Symptom Self-management in Adolescents & Young Adults With Cancer
NCT03265561	Not specified	COMPLETED	Spinal Infection Management With Structural Allograft
NCT04190342	Not specified	COMPLETED	Effects of a Traditional Chinese Exercise Program on Symptom Cluster in Breast Cancer Patients
NCT04874584	Not specified	COMPLETED	Culturally Tailored Nurse Coaching Study for Cancer Symptom Management
NCT04909489	Not specified	UNKNOWN	PDR and SKYD of Dyslipidemia’s Characteristics From the Oxidative Stress Enhancement Caused by Inhibition of Serine Metabolic Pathway
NCT05218122	Not specified	UNKNOWN	Characteristics of LKDS and PBSS of KOA Based on the Enhancement of Inflammatory Response by TGF-β/Smad Pathway Inhibited
NCT05266118	Not specified	COMPLETED	Patient Reported Symptoms the First Week After Intensive Care Unit Discharge and up to Hospital Discharge
NCT05321966	Not specified	COMPLETED	The Effect of Video Training on Symptom Burden Patients Undergoing Hemodialysis Treatment
NCT05818748	Not specified	UNKNOWN	Effect Of Virtual Reality Distraction on Symptom Control and Anxiety in Children With Leukemia
NCT05837988	Not specified	UNKNOWN	Construction of Symptom Network in Maintenance Hemodialysis Patients
NCT06143436	Not specified	UNKNOWN	TCM Constitution, Pattern Types, and Disease Factors in Primary Lung Cancer.
NCT06222008	Not specified	UNKNOWN	Study on Symptom Clusters During Chemotherapy in Ovarian Cancer Patients With Different Chinese Medicine Constitution
NCT06412107	Not specified	COMPLETED	Somatic Acupressure for Symptom Cluster Management in Breast Cancer Survivors
NCT06847360	Not specified	RECRUITING	Home-based Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) for IBS Pain
NCT07281300	Not specified	RECRUITING	Mindfulness-Oriented Respiratory Distress Symptom Intervention for Lung Cancer
NCT07315672	Not specified	RECRUITING	Acupressure for Cough in Lung Cancer Survivors
NCT07479654	Not specified	NOT_YET_RECRUITING	AI-Enabled Frailty Risk Prediction in Adult Congenital Heart Disease
NCT07495358	Not specified	NOT_YET_RECRUITING	Development and Usability Evaluation of a Knowledge Graph-Based Symptom Management System for Patients With Breast Cancer Undergoing Chemotherapy
NCT07576114	Not specified	RECRUITING	Comparison of Gluteal Muscle Activation and Core Strengthening in Dead Butt Syndrome Syndrome
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT01966757	Not specified	COMPLETED	Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT06844877	Not specified	RECRUITING	Italian NCL Registry: a Registry for NCL as an Integration Tool for Future Therapeutic Strategies