PHF21A

Summary

PHF21A (PHD finger protein 21A, HGNC:24156) is a protein-coding gene on chromosome 11p11.2, encoding PHD finger protein 21A (Q96BD5). Component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. It is haploinsufficient (ClinGen: sufficient evidence).

The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002 [PubMed 12032298]).

Source: NCBI Gene 51317 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 405 total — 30 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 36
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001352027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24156
Approved symbol	PHF21A
Name	PHD finger protein 21A
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	BHC80, KIAA1696, BM-006
Ensembl gene	ENSG00000135365
Ensembl biotype	protein_coding
OMIM	608325
Entrez	51317

Gene structure

Transcript identifiers

Ensembl transcripts: 66 — 44 protein_coding, 14 retained_intron, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000323180, ENST00000418153, ENST00000524497, ENST00000525438, ENST00000525676, ENST00000525679, ENST00000527401, ENST00000527753, ENST00000527782, ENST00000528893, ENST00000529734, ENST00000529782, ENST00000530312, ENST00000530587, ENST00000531959, ENST00000532010, ENST00000532028, ENST00000532883, ENST00000533757, ENST00000534724, ENST00000534766, ENST00000676320, ENST00000685188, ENST00000686153, ENST00000687985, ENST00000688222, ENST00000688570, ENST00000688604, ENST00000689695, ENST00000690039, ENST00000690620, ENST00000691784, ENST00000692265, ENST00000692878, ENST00000693049, ENST00000693122, ENST00000863261, ENST00000863262, ENST00000863263, ENST00000863264, ENST00000863265, ENST00000863266, ENST00000863267, ENST00000863268, ENST00000863269, ENST00000863270, ENST00000863271, ENST00000863272, ENST00000863273, ENST00000863274, ENST00000863275, ENST00000863276, ENST00000863277, ENST00000863278, ENST00000863279, ENST00000863280, ENST00000863281, ENST00000863282, ENST00000863283, ENST00000939558, ENST00000939559, ENST00000939560, ENST00000939561, ENST00000960622, ENST00000960623, ENST00000960624

RefSeq mRNA: 10 — MANE Select: NM_001352027 NM_001101802, NM_001352025, NM_001352026, NM_001352027, NM_001352028, NM_001352029, NM_001352030, NM_001352031, NM_001352032, NM_016621

CCDS: CCDS31474, CCDS44578, CCDS91465

Canonical transcript exons

ENST00000676320 — 19 exons

Exon	Start	End
ENSE00000918490	45935636	45935739
ENSE00000988839	45969815	45969904
ENSE00001244659	45971116	45971367
ENSE00001421291	46092183	46092223
ENSE00003496946	45949402	45949481
ENSE00003505519	45979760	45979966
ENSE00003534605	45945840	45946003
ENSE00003609685	45936494	45936569
ENSE00003612590	45948886	45948946
ENSE00003624537	45938157	45938312
ENSE00003646651	45950206	45950257
ENSE00003655755	46084166	46084302
ENSE00003658234	45965315	45965608
ENSE00003665725	45953527	45953625
ENSE00003681895	46079134	46079166
ENSE00003785990	46076754	46076819
ENSE00003899063	46120935	46121454
ENSE00003899647	46090455	46090566
ENSE00003901531	45929319	45934225

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 95.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.8509 / max 488.4674, expressed in 1799 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119503	6.5529	1668
119502	3.8481	1360
119501	3.0619	1279
119500	1.9637	802
119497	0.5988	220
119499	0.3990	179
119498	0.2832	113
119496	0.0726	16
119495	0.0707	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	95.66	gold quality
blood	UBERON:0000178	95.11	gold quality
colonic epithelium	UBERON:0000397	94.66	gold quality
ganglionic eminence	UBERON:0004023	94.06	gold quality
monocyte	CL:0000576	93.88	gold quality
tendon	UBERON:0000043	93.80	gold quality
mononuclear cell	CL:0000842	93.75	gold quality
leukocyte	CL:0000738	93.72	gold quality
buccal mucosa cell	CL:0002336	93.33	gold quality
sural nerve	UBERON:0015488	93.19	gold quality
granulocyte	CL:0000094	93.12	gold quality
ventricular zone	UBERON:0003053	93.12	gold quality
adrenal tissue	UBERON:0018303	92.97	gold quality
cortical plate	UBERON:0005343	92.93	gold quality
calcaneal tendon	UBERON:0003701	92.67	gold quality
medial globus pallidus	UBERON:0002477	92.16	gold quality
mucosa of stomach	UBERON:0001199	92.07	gold quality
corpus callosum	UBERON:0002336	91.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.61	gold quality
left ovary	UBERON:0002119	91.38	gold quality
ovary	UBERON:0000992	91.13	gold quality
right lung	UBERON:0002167	91.03	gold quality
popliteal artery	UBERON:0002250	90.89	gold quality
tibial artery	UBERON:0007610	90.89	gold quality
stromal cell of endometrium	CL:0002255	90.72	gold quality
right ovary	UBERON:0002118	90.55	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.55	gold quality
tonsil	UBERON:0002372	90.45	gold quality
left adrenal gland	UBERON:0001234	90.44	gold quality
left adrenal gland cortex	UBERON:0035825	90.31	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.96
E-CURD-46	no	4.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MBD2

miRNA regulators (miRDB)

239 targeting PHF21A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5692A	100.00	74.40	6850
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-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• Presumably serves as a scaffold protein in BHC in neuronal as well as non-neuronal cells. Possible role in spermatogenesis. (PMID:15325272)
• the recovery of neurosecretion depends on the reciprocal level of BHC80 and REST, with BHC80 working as a negative modulator of REST repression (PMID:19439607)
• we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. (PMID:22770980)
• this case lends further support that haploinsufficiency of PHF21A contributes to the intellectual disability and craniofacial abnormalities in PSS and that there are other genes in the region which likely contribute to the behavioral phenotype in this syndrome. (PMID:28127865)
• Study analyzed by RNA-Sequencing (RNA-Seq) two patient-derived cell lines with heterozygous loss of PHF21A compared to unaffected individuals and identified 1,885 genes that were commonly misregulated. The patient cells displayed down-regulation of key pathways relevant to learning and memory, including Cyclic Adenosine Monophosphate (cAMP)-signaling pathway genes. (PMID:28571721)
• PHF21A truncating mutations were identified in three patients with intellectual disability and craniofacial anomalies. (PMID:30487643)
• RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression. (PMID:30910347)
• PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype. (PMID:31649809)
• PHF21A expression as a biomarker of hepatocellular carcinoma progression and prognosis. (PMID:36305691)
• A novel de novo variant in the PHF21A causes craniofacial abnormalities, intellectual disability and skeletal manifestations. (PMID:36843358)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	phf21aa	ENSDARG00000006878
danio_rerio	phf21ab	ENSDARG00000021378
mus_musculus	Phf21a	ENSMUSG00000058318
rattus_norvegicus	Phf21a	ENSRNOG00000006063

Paralogs (5): ZMYND11 (ENSG00000015171), PHF21B (ENSG00000056487), ZMYND8 (ENSG00000101040), PHF12 (ENSG00000109118), AIRE (ENSG00000160224)

Protein

Protein identifiers

PHD finger protein 21A — Q96BD5 (reviewed: Q96BD5)

Alternative names: BHC80a, BRAF35-HDAC complex protein BHC80

All UniProt accessions (13): A0A1B0GX09, A0A1D5RMU1, Q96BD5, E9PLU5, E9PLV4, E9PNN4, E9PNW9, E9PQM3, E9PR02, E9PS51, H0YCI1, H0YCM5, H0YEK2

UniProt curated annotations — full annotation on UniProt →

Function. Component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it may act as a scaffold. Inhibits KDM1A-mediated demethylation of ‘Lys-4’ of histone H3 in vitro, suggesting a role in demethylation regulation.

Subunit / interactions. Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. In the complex, it interacts directly with HDAC1, HDAC2, HMG20B/BRAF35, KDM1A and RCOR1/CoREST.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in brain. Expressed at lower level in other tissues, including heart, kidney, liver, lung and skeletal muscle. Abundantly expressed in fetal brain.

Disease relevance. Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS) [MIM:618725] An autosomal dominant neurodevelopmental disorder characterized by impaired intellectual development, developmental delay of varying severity, impaired motor skills and language delay. Additional clinical features include macrocephaly, obesity, overgrowth, craniofacial dysmorphism, epilepsy, and variable behavioral manifestations including autism and attention deficit-hyperactivity disorder. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96BD5-1	1	yes
Q96BD5-2	2, hBHC80-4
Q96BD5-3	3

RefSeq proteins (10): NP_001095272, NP_001338954, NP_001338955, NP_001338956, NP_001338957, NP_001338958, NP_001338959, NP_001338960, NP_001338961, NP_057705 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001965	Znf_PHD	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain

Pfam: PF00628

UniProt features (30 total): region of interest 5, compositionally biased region 4, modified residue 3, sequence variant 3, splice variant 2, sequence conflict 2, turn 2, strand 2, helix 2, chain 1, DNA-binding region 1, cross-link 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2PUY	X-RAY DIFFRACTION	1.43
2YQL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BD5-F1	59.12	0.24

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 (4): 350, 444, 447, 65

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214815	HDACs deacetylate histones
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 438 (showing top): AHRARNT_01, GGTGTGT_MIR329, PAX4_01, GNF2_BNIP2, XU_GH1_AUTOCRINE_TARGETS_UP, AAGTCCA_MIR422B_MIR422A, GCANCTGNY_MYOD_Q6, MORF_ATRX, MAZ_Q6, ROVERSI_GLIOMA_COPY_NUMBER_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, TATTATA_MIR374, RACCACAR_AML_Q6, FOXO1_01

GO Biological Process (2): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin organization (GO:0006325)

GO Molecular Function (5): DNA binding (GO:0003677), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): histone deacetylase complex (GO:0000118), nucleoplasm (GO:0005654), DNA repair complex (GO:1990391), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Chromatin modifying enzymes	1
SARS-CoV Infections	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
catalytic complex	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular component organization	1
nucleic acid binding	1
transition metal ion binding	1
cation binding	1
nucleoplasm	1
nuclear protein-containing complex	1
nuclear lumen	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2463 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHF21A	HMG20B	Q9P0W2	998
PHF21A	RCOR1	Q9UKL0	996
PHF21A	KDM1A	O60341	993
PHF21A	HDAC1	Q13547	990
PHF21A	ZNF217	O75362	952
PHF21A	HDAC2	Q92769	925
PHF21A	CTBP1	Q13363	916
PHF21A	H3C14	Q71DI3	826
PHF21A	H3-5	Q6NXT2	826
PHF21A	H3C1	P02295	826
PHF21A	H3-4	Q16695	826
PHF21A	H3-7	Q5TEC6	826
PHF21A	H3-3A	P06351	825
PHF21A	ZMYM2	Q9UBW7	814
PHF21A	ING2	Q9H160	698

IntAct

140 interactions, top by confidence:

A	B	Type	Score
HDAC2	KDM1A	psi-mi:“MI:0914”(association)	0.890
NUP62	PHF21A	psi-mi:“MI:0915”(physical association)	0.870
PHF21A	NUP62	psi-mi:“MI:0915”(physical association)	0.870
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
HDAC1	TNRC18	psi-mi:“MI:0914”(association)	0.790
PHF21A	FHL3	psi-mi:“MI:0915”(physical association)	0.780
FHL3	PHF21A	psi-mi:“MI:0915”(physical association)	0.780
ZYX	PHF21A	psi-mi:“MI:0915”(physical association)	0.740
PHF21A	ZYX	psi-mi:“MI:0915”(physical association)	0.740
HMG20A	KDM1A	psi-mi:“MI:0914”(association)	0.730
HDAC1	ZNF609	psi-mi:“MI:0914”(association)	0.730
PHF21A	TRAF1	psi-mi:“MI:0915”(physical association)	0.670
PHF21A	BANP	psi-mi:“MI:0915”(physical association)	0.670
TRAF1	PHF21A	psi-mi:“MI:0915”(physical association)	0.670
BANP	PHF21A	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (419): PHF21A (Two-hybrid), PHF21A (Two-hybrid), PHF21A (Two-hybrid), PHF21A (Two-hybrid), BANP (Two-hybrid), KRT40 (Two-hybrid), PHF21A (Affinity Capture-MS), PHF21A (Two-hybrid), PHF21A (Proximity Label-MS), PHF21A (Affinity Capture-MS), PHF21A (Affinity Capture-MS), PHF21A (Affinity Capture-MS), PHF21A (Affinity Capture-MS), PHF21A (Affinity Capture-MS), PHF21A (Affinity Capture-MS)

ESM2 similar proteins: A0JME2, A2AUY4, D3ZKB9, D4A666, E1B7L7, F1QZ88, F6NSX9, F8VPJ6, P59759, P78364, Q08CM4, Q0IHV2, Q15723, Q2IBE6, Q2IBF7, Q2QLB3, Q3TUF7, Q4G0F8, Q5DTH5, Q5U4Q0, Q5ZIE8, Q5ZM88, Q63HK5, Q641Z1, Q6P4L9, Q6P4R8, Q6PIJ4, Q6ZPK0, Q6ZSZ6, Q6ZU65, Q76L83, Q7ZUK7, Q7ZUV7, Q80WC1, Q8AYC1, Q8BZ32, Q8C966, Q8CGV9, Q8CHP6, Q8NDX5

Diamond homologs: A0A286Y9D1, A1YVX4, A7E320, B2KF05, B2RRD7, B6CHA3, F4KBP5, F6UA42, G5E8P1, G5EBZ4, O54826, O75164, O94880, O94953, P0CB22, P29375, P34447, P41229, P41230, P47156, P55197, P55198, P55201, Q0P4S5, Q12311, Q20318, Q22516, Q29EQ3, Q30DN6, Q38JA7, Q3UXZ9, Q5E9T7, Q5RD88, Q5TKR9, Q62240, Q6GQJ2, Q6IE81, Q6IE82, Q6IQX0, Q6K431

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PHF21A	“form complex”	“BHC complex”	binding
PHF21A	“down-regulates activity”	KDM1A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
Regulation of PTEN gene transcription	5	13.3×	7e-03
Negative Regulation of CDH1 Gene Transcription	6	10.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	5	13.7×	4e-03
chromatin organization	7	7.1×	5e-03
chromatin remodeling	8	6.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	11
Uncertain significance	165
Likely benign	116
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069464	NM_001352027.3(PHF21A):c.1100_1107del (p.Leu367fs)	Pathogenic
1071405	NM_001352027.3(PHF21A):c.1126_1127del (p.Val376fs)	Pathogenic
1210685	NM_001352027.3(PHF21A):c.1556dup (p.Leu520fs)	Pathogenic
1320144	NM_001352027.3(PHF21A):c.1174A>T (p.Lys392Ter)	Pathogenic
1333273	NM_001352027.3(PHF21A):c.816_823del (p.Thr273fs)	Pathogenic
1457696	NC_000011.9:g.(?45827353)(46401497_?)del	Pathogenic
1708242	NM_001352027.3(PHF21A):c.76C>T (p.Gln26Ter)	Pathogenic
1992308	NM_001352027.3(PHF21A):c.1724C>A (p.Ser575Ter)	Pathogenic
1992361	NM_001352027.3(PHF21A):c.619C>T (p.Gln207Ter)	Pathogenic
2295469	NM_001352027.3(PHF21A):c.602_603del (p.Thr201fs)	Pathogenic
2300672	NM_001352027.3(PHF21A):c.1230dup (p.Lys411Ter)	Pathogenic
2772580	NM_001352027.3(PHF21A):c.373dup (p.Thr125fs)	Pathogenic
3343822	NM_001352027.3(PHF21A):c.1228del (p.Arg410fs)	Pathogenic
3377194	NM_001352027.3(PHF21A):c.265C>T (p.Gln89Ter)	Pathogenic
3383422	NM_001352027.3(PHF21A):c.223C>T (p.Gln75Ter)	Pathogenic
3609679	NM_001352027.3(PHF21A):c.2027del (p.Gln676fs)	Pathogenic
3615120	NM_001352027.3(PHF21A):c.852del (p.Val285fs)	Pathogenic
3654770	NM_001352027.3(PHF21A):c.1144G>T (p.Glu382Ter)	Pathogenic
3775076	NM_001352027.3(PHF21A):c.286C>T (p.Gln96Ter)	Pathogenic
3888281	NM_001352027.3(PHF21A):c.998delinsTCT (p.Thr333fs)	Pathogenic
4627367	NM_001352027.3(PHF21A):c.1251C>G (p.Tyr417Ter)	Pathogenic
4688008	NM_001352027.3(PHF21A):c.1649T>G (p.Leu550Ter)	Pathogenic
4723270	NM_001352027.3(PHF21A):c.16_17del (p.Leu6fs)	Pathogenic
4819818	NM_001352027.3(PHF21A):c.1556del (p.Pro519fs)	Pathogenic
4820148	NM_001352027.3(PHF21A):c.1572_1576delinsAAGA (p.Lys525fs)	Pathogenic
800732	NM_001352027.3(PHF21A):c.1223dup (p.Glu409fs)	Pathogenic
800733	NM_001352027.3(PHF21A):c.660_661insAA (p.Pro221fs)	Pathogenic
800735	NM_001352027.3(PHF21A):c.1288G>A (p.Gly430Ser)	Pathogenic
817590	NM_001352027.3(PHF21A):c.666_667del (p.Pro222_Pro223insTer)	Pathogenic
986205	NM_001352027.3(PHF21A):c.1032_1035del (p.Thr345fs)	Pathogenic

SpliceAI

4836 predictions. Top by Δscore:

Variant	Effect	Δscore
11:45935247:C:CC	acceptor_gain	1.0000
11:45935628:TTACT:T	donor_loss	1.0000
11:45935629:TACTT:T	donor_loss	1.0000
11:45935630:ACTT:A	donor_loss	1.0000
11:45935631:CTTAC:C	donor_loss	1.0000
11:45935632:T:TC	donor_loss	1.0000
11:45935633:TA:T	donor_loss	1.0000
11:45935634:A:AC	donor_gain	1.0000
11:45935635:C:CT	donor_gain	1.0000
11:45935635:CA:C	donor_gain	1.0000
11:45935635:CACT:C	donor_gain	1.0000
11:45935635:CACTT:C	donor_gain	1.0000
11:45935735:TTTTG:T	acceptor_gain	1.0000
11:45935736:TTTG:T	acceptor_gain	1.0000
11:45935737:TTG:T	acceptor_gain	1.0000
11:45935738:TG:T	acceptor_gain	1.0000
11:45935738:TGC:T	acceptor_loss	1.0000
11:45935740:C:CC	acceptor_gain	1.0000
11:45936489:CTTA:C	donor_loss	1.0000
11:45936491:TACCT:T	donor_loss	1.0000
11:45936492:A:AC	donor_gain	1.0000
11:45936492:A:C	donor_loss	1.0000
11:45936493:C:CC	donor_gain	1.0000
11:45936493:CCTG:C	donor_gain	1.0000
11:45936567:CAT:C	acceptor_gain	1.0000
11:45936569:TC:T	acceptor_loss	1.0000
11:45936570:C:CC	acceptor_gain	1.0000
11:45936570:C:CG	acceptor_loss	1.0000
11:45936571:T:A	acceptor_loss	1.0000
11:45948956:T:C	acceptor_gain	1.0000

AlphaMissense

4466 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:45934149:A:G	L621P	1.000
11:45935652:A:G	L590P	1.000
11:45935673:A:G	L583P	1.000
11:45935682:C:G	R580P	1.000
11:45936498:T:A	K559N	1.000
11:45936498:T:G	K559N	1.000
11:45936506:C:G	A557P	1.000
11:45936508:A:T	I556N	1.000
11:45936512:A:C	Y555D	1.000
11:45936512:A:G	Y555H	1.000
11:45936515:A:G	S554P	1.000
11:45936520:A:T	V552D	1.000
11:45936523:A:C	I551S	1.000
11:45936523:A:T	I551N	1.000
11:45936529:A:G	L549S	1.000
11:45936540:C:A	W545C	1.000
11:45936540:C:G	W545C	1.000
11:45936542:A:G	W545R	1.000
11:45936542:A:T	W545R	1.000
11:45938166:A:C	C532W	1.000
11:45938167:C:G	C532S	1.000
11:45938167:C:T	C532Y	1.000
11:45938168:A:G	C532R	1.000
11:45938168:A:T	C532S	1.000
11:45938175:A:C	C529W	1.000
11:45938176:C:A	C529F	1.000
11:45938176:C:G	C529S	1.000
11:45938176:C:T	C529Y	1.000
11:45938177:A:C	C529G	1.000
11:45938177:A:G	C529R	1.000

dbSNP variants (sampled 300 via entrez): RS1000017334 (11:46024830 G>A), RS1000017605 (11:46060650 C>A,T), RS1000059557 (11:46064630 C>A), RS1000072370 (11:46022631 T>C), RS1000091615 (11:46064975 A>G), RS1000100314 (11:45970857 A>G), RS1000114997 (11:46120464 G>A), RS1000132018 (11:46074469 A>G), RS1000140521 (11:46081985 A>G), RS1000150347 (11:46101928 G>A,T), RS1000172038 (11:45929179 G>A), RS1000179045 (11:46011320 C>G), RS1000186028 (11:45985996 G>A), RS1000203049 (11:45928975 G>A), RS1000213546 (11:46057076 T>C)

Disease associations

OMIM: gene MIM:608325 | disease phenotypes: MIM:618725, MIM:214100

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures	Strong	Autosomal dominant
Potocki-Shaffer syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (5): intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (MONDO:0032883), peroxisome biogenesis disorder (MONDO:0019234), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), Potocki-Shaffer syndrome (MONDO:0011022)

Orphanet (3): Peroxisome biogenesis disorder (Orphanet:79189), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000054	Micropenis
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000437	Depressed nasal tip
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000823	Delayed puberty
HP:0001159	Syndactyly
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001357	Plagiocephaly
HP:0001513	Obesity
HP:0001903	Anemia
HP:0001999	Abnormal facial shape
HP:0002667	Nephroblastoma

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000880_3	Menarche (age at onset)	6.000000e-08
GCST002115_15	Axial length	2.000000e-06
GCST002541_87	Menarche (age at onset)	5.000000e-13
GCST005908_33	Height	2.000000e-16
GCST007324_40	Adventurousness	4.000000e-08
GCST008972_93	Urate levels	1.000000e-08
GCST010002_237	Refractive error	1.000000e-10
GCST010244_209	Triglyceride levels	1.000000e-08
GCST010988_416	Adult body size	7.000000e-09
GCST012020_176	Serum metabolite levels	7.000000e-11
GCST012020_205	Serum metabolite levels	3.000000e-14
GCST012020_206	Serum metabolite levels	2.000000e-13
GCST012021_101	Serum metabolite levels	7.000000e-11
GCST012100_19	Hypertrophic cardiomyopathy (sarcomere positive)	9.000000e-10
GCST012226_344	Waist circumference adjusted for body mass index	2.000000e-08
GCST90000025_153	Appendicular lean mass	4.000000e-12
GCST90026416_4	Mild age-related type 2 diabetes	9.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0005318	axial length measurement
EFO:0008579	risk-taking behaviour
EFO:0004531	urate measurement
EFO:0004530	triglyceride measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536664	Peroxisome biogenesis disorders (supp.)
C538356	Potocki-Shaffer syndrome (supp.)
C531857	Zellweger leukodystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Arsenic Trioxide	increases expression	2
Tretinoin	increases expression	2
Cadmium Chloride	increases abundance, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
geraniol	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Endosulfan	increases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Melphalan	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Nicotine	increases expression	1
Dronabinol	increases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Valproic Acid	decreases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01838941	PHASE3	COMPLETED	Betaine and Peroxisome Biogenesis Disorders
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD