TBCE

Summary

TBCE (tubulin folding cofactor E, HGNC:11582) is a protein-coding gene on chromosome 1q42.3, encoding Tubulin-specific chaperone E (Q15813). Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation. It is a selective cancer dependency (DepMap: 57.3% of cell lines).

Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 6905 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypoparathyroidism-retardation-dysmorphism syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 538 total — 50 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 103
• Cancer dependency (DepMap): dependent in 57.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003193

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11582
Approved symbol	TBCE
Name	tubulin folding cofactor E
Location	1q42.3
Locus type	gene with protein product
Status	Approved
Aliases	KCS1, pac2
Ensembl gene	ENSG00000284770
Ensembl biotype	protein_coding
OMIM	604934
Entrez	6905

Gene structure

Transcript identifiers

Ensembl transcripts: 66 — 30 nonsense_mediated_decay, 19 protein_coding, 13 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000366601, ENST00000406207, ENST00000461651, ENST00000465463, ENST00000472011, ENST00000482230, ENST00000543662, ENST00000642339, ENST00000642372, ENST00000642463, ENST00000642610, ENST00000642764, ENST00000642926, ENST00000642981, ENST00000643125, ENST00000643142, ENST00000643238, ENST00000643487, ENST00000643524, ENST00000643615, ENST00000643993, ENST00000643994, ENST00000644037, ENST00000644126, ENST00000644217, ENST00000644265, ENST00000644578, ENST00000644625, ENST00000644838, ENST00000644910, ENST00000645372, ENST00000645551, ENST00000645582, ENST00000645662, ENST00000645899, ENST00000645964, ENST00000646104, ENST00000646186, ENST00000646286, ENST00000646384, ENST00000646463, ENST00000646495, ENST00000646536, ENST00000646661, ENST00000646821, ENST00000646842, ENST00000646848, ENST00000646929, ENST00000647151, ENST00000647233, ENST00000647322, ENST00000647332, ENST00000647338, ENST00000647407, ENST00000647418, ENST00000647489, ENST00000651186, ENST00000883450, ENST00000883451, ENST00000883452, ENST00000920585, ENST00000920586, ENST00000920587, ENST00000920588, ENST00000920589, ENST00000954613

RefSeq mRNA: 4 — MANE Select: NM_003193 NM_001079515, NM_001287801, NM_001287802, NM_003193

CCDS: CCDS1605, CCDS73052, CCDS86060

Canonical transcript exons

ENST00000642610 — 17 exons

Exon	Start	End
ENSE00001069482	235419473	235419561
ENSE00003506011	235414433	235414618
ENSE00003526070	235430705	235430804
ENSE00003531800	235434204	235434280
ENSE00003547512	235427140	235427239
ENSE00003597744	235436544	235436608
ENSE00003617305	235380019	235380149
ENSE00003629969	235442852	235442911
ENSE00003646583	235441814	235441882
ENSE00003658869	235436386	235436450
ENSE00003668563	235437322	235437474
ENSE00003671364	235401503	235401587
ENSE00003679627	235448349	235448440
ENSE00003680028	235435745	235435840
ENSE00003685900	235438769	235438922
ENSE00003815943	235448670	235452443
ENSE00003849090	235367427	235367504

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 91.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3102 / max 421.0361, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9187	24.6998	1816
9182	22.7264	1798
9184	0.4714	180
9186	0.1390	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	91.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.66	gold quality
cortical plate	UBERON:0005343	91.33	gold quality
right lobe of thyroid gland	UBERON:0001119	90.83	gold quality
ganglionic eminence	UBERON:0004023	90.74	gold quality
gastrocnemius	UBERON:0001388	90.70	gold quality
muscle of leg	UBERON:0001383	90.28	gold quality
skeletal muscle tissue	UBERON:0001134	90.20	gold quality
thyroid gland	UBERON:0002046	90.18	gold quality
mucosa of transverse colon	UBERON:0004991	90.12	gold quality
left lobe of thyroid gland	UBERON:0001120	89.84	gold quality
cerebellar cortex	UBERON:0002129	89.54	gold quality
cerebellar hemisphere	UBERON:0002245	89.54	gold quality
cerebellum	UBERON:0002037	89.42	gold quality
primary visual cortex	UBERON:0002436	89.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.09	gold quality
lower esophagus mucosa	UBERON:0035834	89.09	gold quality
muscle tissue	UBERON:0002385	88.89	gold quality
right lobe of liver	UBERON:0001114	88.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.70	gold quality
heart left ventricle	UBERON:0002084	88.44	gold quality
hypothalamus	UBERON:0001898	87.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.72	gold quality
tibial nerve	UBERON:0001323	87.54	gold quality
adrenal tissue	UBERON:0018303	87.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.46	gold quality
heart	UBERON:0000948	87.39	gold quality
right ovary	UBERON:0002118	87.36	gold quality
granulocyte	CL:0000094	87.32	gold quality
right adrenal gland	UBERON:0001233	87.30	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-CURD-10	no	524.72
E-GEOD-99795	no	113.65
E-ANND-3	no	3.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting TBCE, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-6780B-3P	99.13	67.18	622
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-15B-3P	97.85	66.68	974
HSA-MIR-4640-3P	94.58	63.02	263
HSA-MIR-4664-3P	88.57	63.79	80

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 57.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• TBCE has a role in membrane trafficking in the Golgi and late endosomal compartments, tubulin assembly, and the development of the parathyroid (PMID:12389028)
• Tbce is critical for the maintenance of microtubules in mouse motor axons (PMID:12389029)
• The tubulin-specific chaperone E (Tbce) mutation described here suggests that alterations in tubulin assembly lead to retrograde degeneration of motor axons, ultimately resulting in motoneuron cell death. (PMID:12446740)
• Reviews recent findings on the molecular mechanisms of the development of the parathyroid glands, with special emphasis on the possible role of tubulin chaperone E (TBCE), implicated in the hypopathyroidism, retardation and dysmorphism (HRD) syndrome. (PMID:17008776)
• TBCE, TBCB and alpha-tubulin form a ternary complex after heterodimer dissociation. These complexes might serve to escort alpha-tubulin towards degradation or recycling, depending on the cell requirements. (PMID:17184771)
• Depletion of Op18 by means of RNA interference increased the susceptibility of tubulin to TBCE or E-like mediated disruption, while overexpressed Op18 exerted a tubulin-protective effect. (PMID:18262179)
• Study demonstrates that, unlike its counterpart TBCE, TBCB only moderately destabilizes microtubules. (PMID:19168853)
• TBCE is required for the normal development and function of neuromuscular synapses and that it promotes microtubule formation (PMID:19297412)
• TBCE may play a role in development of the anterior pituitary, corpus callosum, and white matter in addition to the parathyroid glands. (PMID:19491227)
• tudies confirmed elevated expression of three target antigens RAB38, TBCE, and DUSP12 in CML. (PMID:20103624)
• the role of the human TBCE and TBCB chaperones in alpha-tubulin-beta-tubulin dissociation, was investigated. (PMID:25908846)
• Sanjad-Sakati syndrome molecular pathology has been shown to be due to mutations in the TBCE gene on chromosome 1q42-q43. (PMID:26231322)
• Although loss of function of TBCE has been documented to impact multiple developmental processes, the present findings provide evidence that hypomorphic TBCE mutations primarily drive neurodegeneration (PMID:27666369)
• TBCE protein was localized in the middle region and in the tail of the sperm while in the oocyte the localization was cytosolic. (PMID:28583220)
• Mutation analysis of the TBCE gene revealed the common 12-bp (155-166del) deletion in three new Sanjad-Sakati syndrome patients from Tunisia. (PMID:30638765)
• Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations. (PMID:32275946)
• Hypoparathyroidism-Retardation-Dysmorphism Syndrome due to a Variant in the Tubulin-Specific Chaperone E Gene as a Cause of Combined Immune Deficiency. (PMID:36258138)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbce	ENSDARG00000099921
mus_musculus	Tbce	ENSMUSG00000039233
rattus_norvegicus	Tbce	ENSRNOG00000029667
drosophila_melanogaster	Tbce	FBGN0033055
caenorhabditis_elegans		WBGENE00019503

Paralogs (1): TBCEL (ENSG00000154114)

Protein

Protein identifiers

Tubulin-specific chaperone E — Q15813 (reviewed: Q15813)

Alternative names: Tubulin-folding cofactor E

All UniProt accessions (24): Q15813, A0A2R8Y3S1, A0A2R8Y4E7, A0A2R8Y4P2, A0A2R8Y4V6, A0A2R8Y597, A0A2R8Y5H6, A0A2R8Y5Q8, A0A2R8Y6G3, A0A2R8Y6L2, A0A2R8Y6Q1, A0A2R8Y720, A0A2R8Y784, A0A2R8Y787, A0A2R8Y7E7, A0A2R8Y7H8, A0A2R8Y809, A0A2R8Y897, A0A2R8YER9, A0A2R8YFG9, A0A2R8YFM3, A0A2R8YH53, A0A2R8YHI9, A0A2U3TZJ6

UniProt curated annotations — full annotation on UniProt →

Function. Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation. Required for correct organization of microtubule cytoskeleton and mitotic splindle, and maintenance of the neuronal microtubule network.

Subunit / interactions. Supercomplex made of cofactors A to E. Cofactors A and D function by capturing and stabilizing tubulin in a quasi-native conformation. Cofactor E binds to the cofactor D-tubulin complex; interaction with cofactor C then causes the release of tubulin polypeptides that are committed to the native state. Cofactors B and E can form a heterodimer which binds to alpha-tubulin and enhances their ability to dissociate tubulin heterodimers. Interacts with TBCD.

Subcellular location. Cytoplasm. Cytoskeleton.

Disease relevance. Hypoparathyroidism-retardation-dysmorphism syndrome (HRDS) [MIM:241410] An autosomal recessive multisystem disorder characterized by hypoparathyroidism, intrauterine and postnatal growth retardation, psychomotor retardation, epilepsy, microcephaly, and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry. Kenny-Caffey syndrome 1 (KCS1) [MIM:244460] An autosomal recessive form of Kenny-Caffey syndrome, a disorder characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. Clinical features include cortical thickening and medullary stenosis of the tubular bones, delayed closure of fontanels, defective dentition, small eyes with hypermetropia, and frontal bossing with a triangular face. The disease is caused by variants affecting the gene represented in this entry. Encephalopathy, progressive, with amyotrophy and optic atrophy (PEAMO) [MIM:617207] An autosomal recessive, progressive, neurodegenerative encephalopathy with onset in infancy. Affected individuals manifest delayed psychomotor development, severe hypotonia, motor regression, spinal muscular atrophy, distal amyotrophy and weakness of all limbs, and intellectual disability of variable severity. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TBCE family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15813-1	1	yes
Q15813-2	2

RefSeq proteins (4): NP_001072983, NP_001274730, NP_001274731, NP_003184* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR000938	CAP-Gly_domain	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036859	CAP-Gly_dom_sf	Homologous_superfamily
IPR044079	Ubl_TBCE	Domain

Pfam: PF01302, PF14560

UniProt features (30 total): repeat 7, sequence variant 5, strand 4, helix 4, modified residue 3, domain 2, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4ICV	X-RAY DIFFRACTION	1.45
9M1J	ELECTRON MICROSCOPY	2.14
9M1M	ELECTRON MICROSCOPY	2.21
4ICU	X-RAY DIFFRACTION	2.4
9M1K	ELECTRON MICROSCOPY	2.45
9M1L	ELECTRON MICROSCOPY	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15813-F1	89.27	0.72

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 (3): 2, 463, 495

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-389977	Post-chaperonin tubulin folding pathway
R-HSA-391251	Protein folding
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 0 (showing top):

GO Biological Process (12): microtubule cytoskeleton organization (GO:0000226), protein folding (GO:0006457), tubulin complex assembly (GO:0007021), post-chaperonin tubulin folding pathway (GO:0007023), mitotic spindle organization (GO:0007052), adult locomotory behavior (GO:0008344), post-embryonic development (GO:0009791), muscle atrophy (GO:0014889), developmental growth (GO:0048589), peripheral nervous system neuron axonogenesis (GO:0048936), translation (GO:0006412), axonogenesis (GO:0007409)

GO Molecular Function (4): alpha-tubulin binding (GO:0043014), protein-folding chaperone binding (GO:0051087), structural constituent of ribosome (GO:0003735), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), microtubule (GO:0005874), ribosome (GO:0005840), cytoskeleton (GO:0005856), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein folding	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	2
cytoskeleton organization	1
microtubule-based process	1
cellular process	1
protein maturation	1
protein-containing complex assembly	1
tubulin complex assembly	1
mitotic cell cycle	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
locomotory behavior	1
adult behavior	1
multicellular organism development	1
multicellular organismal process	1
muscle adaptation	1
developmental process	1
growth	1
axonogenesis	1
peripheral nervous system neuron development	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
tubulin binding	1
protein binding	1
structural molecule activity	1
ribosome	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
protein-containing complex	1

Protein interactions and networks

STRING

924 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBCE	TBCD	Q9BTW9	950
TBCE	FAM111A	Q96PZ2	950
TBCE	CPN1	P15169	769
TBCE	TBCB	Q99426	735
TBCE	SYVN1	Q86TM6	717
TBCE	BRCA1	P38398	669
TBCE	SEL1L	Q9UBV2	660
TBCE	BRCA2	P51587	650
TBCE	PARP1	P09874	645
TBCE	PPIP5K1	Q6PFW1	598
TBCE	PALB2	Q86YC2	581
TBCE	TBCC	Q15814	576
TBCE	ARL2	P36404	564
TBCE	VCP	P55072	547
TBCE	TBCA	O75347	536

IntAct

55 interactions, top by confidence:

A	B	Type	Score
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
NFKBIA	POLRMT	psi-mi:“MI:0914”(association)	0.670
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
BHMT2	INPPL1	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
CLCC1	PLSCR1	psi-mi:“MI:0914”(association)	0.530
ZFC3H1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.530
SFTA2	TBCE	psi-mi:“MI:0914”(association)	0.530
DIRAS1	UNC13B	psi-mi:“MI:0914”(association)	0.500
SERBP1	TBCE	psi-mi:“MI:0915”(physical association)	0.400
LRRK2		psi-mi:“MI:0914”(association)	0.350
ZFC3H1	ANKHD1	psi-mi:“MI:0914”(association)	0.350
TRIM11	BTN3A3	psi-mi:“MI:0914”(association)	0.350
CLCC1	PLSCR1	psi-mi:“MI:0914”(association)	0.350
SFTA2	SEPTIN2	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TNFRSF10A	psi-mi:“MI:0914”(association)	0.350
TUBB4B	TUBA1B	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
TRIM11	RABGAP1L	psi-mi:“MI:0914”(association)	0.350
FGB	KIF2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (89): TUB1 (Reconstituted Complex), RPN10 (Reconstituted Complex), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Co-fractionation), TBCE (Affinity Capture-MS), TBCE (Proximity Label-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS), TBCE (Affinity Capture-MS)

ESM2 similar proteins: A0JM56, A0JPI9, A2BFL2, A5PK13, A6H639, J9SQF3, O13066, P19686, P33402, Q02108, Q0VAA2, Q14BP6, Q15111, Q15813, Q3USB7, Q498T9, Q4R642, Q4V8D9, Q4ZHS0, Q5DU41, Q5FVQ9, Q5RAG3, Q5RBD9, Q5RJH2, Q5ZIJ9, Q5ZIU8, Q62688, Q68F79, Q6DN12, Q6GQN5, Q6NU09, Q6P9F7, Q6WRX3, Q7Z7L7, Q80ZJ6, Q8BG40, Q8CDU4, Q8CIR4, Q8CIV8, Q8HXA6

Diamond homologs: A1Z6J5, P13496, Q01397, Q15813, Q32KS0, Q5E951, Q5FVQ9, Q5RBD9, Q5U378, Q5U508, Q67Z52, Q8CIV8, Q99426, Q9D1E6, A0A287B8J2, B9EHT4, E9Q309, O08788, O42184, O42667, O55156, P28023, P30622, P33420, P34531, P35458, Q10235, Q14203, Q20728, Q54Z01, Q55CN0, Q5R686, Q5U243, Q5VT06, Q66HD5, Q6PCJ1, Q8CI96, Q8GRL7, Q8N3C7, Q922J3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	18
Uncertain significance	132
Likely benign	226
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1007432	NC_000001.10:g.(?235543365)(235543474_?)del	Pathogenic
1374332	NC_000001.10:g.(?235594000)(235606246_?)del	Pathogenic
1490158	NC_000001.10:g.(?235543365)(235922919_?)del	Pathogenic
2275948	NM_003193.5(TBCE):c.653G>A (p.Trp218Ter)	Pathogenic
2424651	NC_000001.10:g.(?235564798)(235564922_?)del	Pathogenic
2424652	NC_000001.10:g.(?235597499)(235597615_?)del	Pathogenic
2700658	NM_003193.5(TBCE):c.961C>T (p.Gln321Ter)	Pathogenic
2718164	NM_003193.5(TBCE):c.654G>A (p.Trp218Ter)	Pathogenic
2733081	NM_003193.5(TBCE):c.626T>G (p.Leu209Ter)	Pathogenic
2749172	NM_003193.5(TBCE):c.733G>T (p.Glu245Ter)	Pathogenic
2759574	NM_003193.5(TBCE):c.1253del (p.Tyr418fs)	Pathogenic
2762704	NM_003193.5(TBCE):c.1225G>T (p.Glu409Ter)	Pathogenic
2781038	NM_003193.5(TBCE):c.373C>T (p.Gln125Ter)	Pathogenic
2786232	NM_003193.5(TBCE):c.700del (p.Leu234fs)	Pathogenic
2792510	NM_003193.5(TBCE):c.1228G>T (p.Glu410Ter)	Pathogenic
2803503	NM_003193.5(TBCE):c.1090C>T (p.Gln364Ter)	Pathogenic
2807938	NM_003193.5(TBCE):c.1156C>T (p.Arg386Ter)	Pathogenic
2809140	NM_003193.5(TBCE):c.470del (p.Lys157fs)	Pathogenic
2829032	NM_003193.5(TBCE):c.908dup (p.Ser304fs)	Pathogenic
2839180	NM_003193.5(TBCE):c.500_501insCCATGATGAAAAACCTGTTGTCATC (p.Trp168fs)	Pathogenic
2847690	NM_003193.5(TBCE):c.836T>G (p.Leu279Ter)	Pathogenic
2868743	NM_003193.5(TBCE):c.757_760del (p.Thr253fs)	Pathogenic
2870059	NM_003193.5(TBCE):c.22del (p.Asp8fs)	Pathogenic
2954608	NM_003193.5(TBCE):c.1063C>T (p.Arg355Ter)	Pathogenic
2958887	NM_003193.5(TBCE):c.1025del (p.Asn342fs)	Pathogenic
3000673	NM_003193.5(TBCE):c.1183del (p.Gln395fs)	Pathogenic
3001983	NM_003193.5(TBCE):c.195del (p.Gly66fs)	Pathogenic
3247949	NC_000001.10:g.(?235602064)(235602257_?)del	Pathogenic
3247950	NC_000001.10:g.(?235582768)(235582896_?)del	Pathogenic
3247952	NC_000001.10:g.(?235590435)(235590574_?)del	Pathogenic

SpliceAI

2749 predictions. Top by Δscore:

Variant	Effect	Δscore
1:235367503:AG:A	donor_loss	1.0000
1:235367504:GGT:G	donor_loss	1.0000
1:235367505:GTG:G	donor_loss	1.0000
1:235367506:T:A	donor_loss	1.0000
1:235380013:TCCTA:T	acceptor_loss	1.0000
1:235380014:CCTAG:C	acceptor_loss	1.0000
1:235380015:CTAG:C	acceptor_loss	1.0000
1:235380016:TA:T	acceptor_loss	1.0000
1:235380017:A:AG	acceptor_gain	1.0000
1:235380017:A:T	acceptor_loss	1.0000
1:235380018:G:GA	acceptor_gain	1.0000
1:235380018:G:T	acceptor_loss	1.0000
1:235380018:GA:G	acceptor_gain	1.0000
1:235380018:GAT:G	acceptor_gain	1.0000
1:235380018:GATC:G	acceptor_gain	1.0000
1:235380018:GATCT:G	acceptor_gain	1.0000
1:235380116:G:GG	donor_gain	1.0000
1:235380145:GGCAG:G	donor_gain	1.0000
1:235380146:GCAG:G	donor_gain	1.0000
1:235380146:GCAGG:G	donor_gain	1.0000
1:235380147:CAGGT:C	donor_loss	1.0000
1:235380150:G:GG	donor_gain	1.0000
1:235380150:G:T	donor_loss	1.0000
1:235414428:A:AG	acceptor_gain	1.0000
1:235414428:ACCAG:A	acceptor_gain	1.0000
1:235414429:C:G	acceptor_gain	1.0000
1:235414429:CCAG:C	acceptor_loss	1.0000
1:235414431:A:AG	acceptor_gain	1.0000
1:235414431:A:G	acceptor_loss	1.0000
1:235414431:AG:A	acceptor_gain	1.0000

AlphaMissense

3410 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:235401523:T:A	W41R	0.995
1:235401523:T:C	W41R	0.995
1:235401525:G:C	W41C	0.995
1:235401525:G:T	W41C	0.995
1:235401577:T:C	F59L	0.990
1:235401579:T:A	F59L	0.990
1:235401579:T:G	F59L	0.990
1:235380122:T:C	F25L	0.987
1:235380124:T:A	F25L	0.987
1:235380124:T:G	F25L	0.987
1:235401554:G:A	G51E	0.982
1:235401524:G:C	W41S	0.979
1:235401524:G:T	W41L	0.979
1:235427168:C:A	N163K	0.979
1:235427168:C:G	N163K	0.979
1:235401553:G:T	G51W	0.978
1:235414447:G:A	G67E	0.975
1:235427181:T:A	W168R	0.975
1:235427181:T:C	W168R	0.975
1:235401508:T:A	W36R	0.974
1:235401508:T:C	W36R	0.974
1:235430796:T:A	W218R	0.974
1:235430796:T:C	W218R	0.974
1:235380111:C:A	A21E	0.970
1:235401578:T:C	F59S	0.970
1:235380090:T:A	V14D	0.966
1:235401549:T:A	H49Q	0.966
1:235401549:T:G	H49Q	0.966
1:235401546:G:C	K48N	0.965
1:235401546:G:T	K48N	0.965

dbSNP variants (sampled 300 via entrez): RS1000072102 (1:235384992 G>A), RS1000137041 (1:235382376 C>G,T), RS1000140732 (1:235423896 C>T), RS1000161199 (1:235378858 C>T), RS1000186396 (1:235427363 G>A), RS1000193028 (1:235413678 A>G,T), RS1000196548 (1:235372219 G>C), RS1000255764 (1:235378218 GTTTT>G,GTTT), RS1000367060 (1:235366795 C>A), RS1000403522 (1:235429402 G>A), RS1000451544 (1:235452460 T>C), RS1000479561 (1:235402243 T>C), RS1000495812 (1:235440128 A>G,T), RS1000501373 (1:235449699 A>G), RS1000535455 (1:235412880 C>T)

Disease associations

OMIM: gene MIM:604934 | disease phenotypes: MIM:617207, MIM:241410, MIM:244460, MIM:214500, MIM:615181

GenCC curated gene-disease

Disease	Classification	Inheritance
hypoparathyroidism-retardation-dysmorphism syndrome	Definitive	Autosomal recessive
encephalopathy, progressive, with amyotrophy and optic atrophy	Strong	Autosomal recessive
early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	Strong	Autosomal recessive
autosomal recessive Kenny-Caffey syndrome	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
encephalopathy, progressive, with amyotrophy and optic atrophy	Moderate	AR

Mondo (8): encephalopathy, progressive, with amyotrophy and optic atrophy (MONDO:0014968), hypoparathyroidism-retardation-dysmorphism syndrome (MONDO:0009426), autosomal recessive Kenny-Caffey syndrome (MONDO:0009486), Chediak-Higashi syndrome (MONDO:0008963), pituitary stalk interruption syndrome (MONDO:0019828), disorder of sexual differentiation (MONDO:0002145), muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11 (MONDO:0014071), early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (MONDO:0044646)

Orphanet (8): Sanjad-Sakati syndrome (Orphanet:2323), Kenny-Caffey syndrome (Orphanet:2333), Autosomal recessive Kenny-Caffey syndrome (Orphanet:93324), Chédiak-Higashi syndrome (Orphanet:167), Pituitary stalk interruption syndrome (Orphanet:95496), Difference of sex development (Orphanet:90771), Muscle-eye-brain disease (Orphanet:588), Walker-Warburg syndrome (Orphanet:899)

HPO phenotypes

103 total (30 of 103 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000164	Abnormality of the dentition
HP:0000193	Bifid uvula
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000444	Convex nasal ridge
HP:0000483	Astigmatism
HP:0000490	Deeply set eye
HP:0000568	Microphthalmia
HP:0000648	Optic atrophy
HP:0000670	Carious teeth
HP:0000682	Abnormal dental enamel morphology
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000829	Hypoparathyroidism
HP:0000883	Thin ribs
HP:0000890	Long clavicles
HP:0001249	Intellectual disability
HP:0001250	Seizure

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000428_4	Adiposity	3.000000e-07
GCST006585_2235	Blood protein levels	2.000000e-09
GCST009524_44	Household income (MTAG)	8.000000e-10
GCST011107_2	First year height change in growth hormone-treated short stature	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009695	household income
EFO:0010969	response to growth hormone

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002609	Chediak-Higashi Syndrome	C11.270.040.772; C15.378.553.774.257; C16.320.798.375; C20.673.774.257; C20.673.795.375
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
C537157	Hypoparathyroidism-retardation-dysmorphism syndrome (supp.)
C537021	Kenny-Caffey syndrome, Type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
bufotalin	decreases expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
arsenite	increases reaction, affects binding	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
acyline	increases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Fluorouracil	affects response to substance	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT02789332	PHASE2	COMPLETED	Assessing the Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel / Carboplatin Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With HER2-negative Early Breast Cancer and Homologous Recombination Deficiency
NCT03740893	PHASE2	RECRUITING	PHOENIX DDR/Anti-PD-L1 Trial: A Pre-surgical Window of Opportunity and Post-surgical Adjuvant Biomarker Study of DNA Damage Response Inhibition With or Without Anti-PD-L1 Immunotherapy in Patients With Neoadjuvant Treatment Resistant Residual Triple Negative Breast Cancer
NCT04895046	PHASE2	WITHDRAWN	Maintenance Niraparib and Dostarlimab in Advanced Cholangiocarcinoma
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT03415659	PHASE1	UNKNOWN	Phase I Clinical Study of HWH340 Tablet in Patients With Advanced Solid Tumors
NCT07156253	PHASE1	RECRUITING	Study of SYN818 With Olaparib for the Treatment of Locally Advanced or Metastatic Solid Tumors
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT05044091	Not specified	UNKNOWN	Homologous Recombination Deficiency in Chinese Ovarian Cancer Patients
NCT05069818	Not specified	UNKNOWN	Variance of HRD From Paired Ovarian Cancer
NCT00176826	PHASE2/PHASE3	TERMINATED	T-Cell Depletion and Stem Cell Transplant for Immune Deficiencies and Histiocytic Disorders
NCT00730314	PHASE1/PHASE2	COMPLETED	Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells
NCT00005917	Not specified	RECRUITING	Study of Chediak-Higashi Syndrome
NCT00005933	Not specified	COMPLETED	Learning and Behavior Problems in Children With Chronic Granulomatous Disease and Related Disorders
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006056	Not specified	UNKNOWN	Pilot Study of Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Life Threatening Hemophagocytic Disorders
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions