ASXL3

Summary

ASXL3 (ASXL transcriptional regulator 3, HGNC:29357) is a protein-coding gene on chromosome 18q12.1, encoding Putative Polycomb group protein ASXL3 (Q9C0F0). Putative Polycomb group (PcG) protein. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein containing a plant homeodomain (PHD) zinc finger domain that plays a role in the regulation of gene transcription. The encoded protein has been shown to negatively regulate lipogenesis by binding to and inhibiting the transcriptional activity of two nuclear hormone receptors, oxysterols receptor LXR-alpha (LXRalpha) and thyroid hormone receptor beta (TRbeta). The encoded protein may also inhibit histone deubiquitination. Mutations in this gene have been identified in human patients with Bainbridge-Ropers syndrome, which is characterized by feeding difficulties, developmental delay and other features.

Source: NCBI Gene 80816 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 1,030 total — 136 pathogenic, 91 likely-pathogenic
• Phenotypes (HPO): 107
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_030632

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29357
Approved symbol	ASXL3
Name	ASXL transcriptional regulator 3
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141431
Ensembl biotype	protein_coding
OMIM	615115
Entrez	80816

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding_CDS_not_defined, 4 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000269197, ENST00000585426, ENST00000586327, ENST00000586948, ENST00000588038, ENST00000590189, ENST00000590225, ENST00000590973, ENST00000592288, ENST00000592349, ENST00000592541, ENST00000593195, ENST00000593235, ENST00000642541, ENST00000647014, ENST00000681521, ENST00000696964

RefSeq mRNA: 1 — MANE Select: NM_030632 NM_030632

CCDS: CCDS45847

Canonical transcript exons

ENST00000269197 — 12 exons

Exon	Start	End
ENSE00000948514	33742888	33751195
ENSE00001542917	33683405	33683568
ENSE00001542918	33671747	33671866
ENSE00001542919	33670673	33670790
ENSE00002796162	33578219	33578685
ENSE00003541683	33731968	33732064
ENSE00003554065	33734310	33734415
ENSE00003592124	33644894	33645002
ENSE00003608985	33607594	33607676
ENSE00003624249	33646245	33646353
ENSE00003631966	33738487	33740443
ENSE00003783981	33661616	33661737

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 97.24.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7567 / max 72.0888, expressed in 247 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169878	0.7102	242
169880	0.0377	11
169881	0.0089	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.24	gold quality
secondary oocyte	CL:0000655	92.40	gold quality
cortical plate	UBERON:0005343	91.31	gold quality
sperm	CL:0000019	88.62	gold quality
oocyte	CL:0000023	85.60	gold quality
male germ cell	CL:0000015	85.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.86	gold quality
ganglionic eminence	UBERON:0004023	82.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.16	gold quality
middle temporal gyrus	UBERON:0002771	81.98	gold quality
embryo	UBERON:0000922	78.09	gold quality
sural nerve	UBERON:0015488	75.54	gold quality
endothelial cell	CL:0000115	75.37	silver quality
ventricular zone	UBERON:0003053	75.35	gold quality
superior frontal gyrus	UBERON:0002661	75.32	gold quality
entorhinal cortex	UBERON:0002728	74.49	gold quality
postcentral gyrus	UBERON:0002581	74.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.05	gold quality
primary visual cortex	UBERON:0002436	73.78	gold quality
testis	UBERON:0000473	73.51	gold quality
corpus callosum	UBERON:0002336	73.50	gold quality
choroid plexus epithelium	UBERON:0003911	72.53	gold quality
islet of Langerhans	UBERON:0000006	72.50	gold quality
left testis	UBERON:0004533	72.43	gold quality
right testis	UBERON:0004534	72.27	gold quality
parietal lobe	UBERON:0001872	72.21	gold quality
Brodmann (1909) area 46	UBERON:0006483	71.80	silver quality
colonic epithelium	UBERON:0000397	71.04	gold quality
blood vessel layer	UBERON:0004797	70.99	gold quality
germinal epithelium of ovary	UBERON:0001304	70.72	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	14.82
E-GEOD-83139	yes	11.20
E-ENAD-27	yes	7.76
E-ANND-3	yes	6.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, EZH2, HOXA11

miRNA regulators (miRDB)

280 targeting ASXL3, 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-9-5P	100.00	72.28	2361
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-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 17)

• data suggest that ASXL3 is another corepressor of LXRalpha, promoting to the regulation of lipid homeostasis (PMID:25450400)
• ASXL1, ASXL2 and ASXL3 are epigenetic scaffold proteins that are involved in the pathogenesis of non-cancerous diseases and cancers.[Review] (PMID:25835095)
• in contrast with ASXL1 and ASXL2 mutations, ASXL3 mutations were rare events within t(8;21)-AML patients. (PMID:25856206)
• De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. (PMID:26647312)
• Our findings suggest that the expression of the truncated ASXL3 protein, including ASXN and ASXH domains, give rise to Bainbridge-Ropers syndrome , which is distinct from but overlaps with Bohring-Opitz syndrome (PMID:27075689)
• Loss-of-function variants in ASXL3 identified as causal for Bainbridge-Ropers syndrome. (PMID:27901041)
• A second mutation cluster region within ASXL3 in older patients with Bainbridge-Ropers syndrome expands the phenotypic spectrum of the disorder and highlights its high frequency. (PMID:28100473)
• Data indicate that ASXL3 was markedly upregulated in lung iPSCs (Lu-iPSC) and small cell lung cancer (SCLC) lines and clinical specimens. (PMID:28935813)
• Truncating de novo mutations in ASXL3 cause Bainbridge-Ropers syndrome (BRPS), a developmental disorder with similarities to Bohring-Opitz syndrome. to our knowledge, this is the first report of the disorder in two related individuals. Our findings lend further support to intellectual disability, absent speech, autistic traits, hypotonia, and distinctive facial appearance as common emerging features of Bainbridge-Ropers f (PMID:29305346)
• Somatic mutations in AZXL3 were associated with sporadic parathyroid adenomas in a Chinese population. (PMID:29982334)
• Mosaicism in ASXL3-related syndrome: Description of five patients from three families. (PMID:32240826)
• ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer. (PMID:32669118)
• Compound heterozygous mutation of the ASXL3 gene causes autosomal recessive congenital heart disease. (PMID:32696347)
• Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions. (PMID:33242595)
• Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. (PMID:33751773)
• Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3. (PMID:34436830)
• Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype. (PMID:36177608)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Asxl3	ENSMUSG00000045215
rattus_norvegicus	Asxl3	ENSRNOG00000015383
drosophila_melanogaster	Asx	FBGN0261823

Paralogs (2): ASXL2 (ENSG00000143970), ASXL1 (ENSG00000171456)

Protein

Protein identifiers

Putative Polycomb group protein ASXL3 — Q9C0F0 (reviewed: Q9C0F0)

Alternative names: Additional sex combs-like protein 3

All UniProt accessions (7): A0A2R8Y461, A0A7P0TAE5, A0A8V8TKV8, Q9C0F0, K7EJ76, K7ELG8, K7EMU6

UniProt curated annotations — full annotation on UniProt →

Function. Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility. Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-119’ (H2AK119ub1). The PR-DUB complex is an epigenetic regulator of gene expression and acts as a transcriptional coactivator, affecting genes involved in development, cell communication, signaling, cell proliferation and cell viability. ASXL1, ASXL2 and ASXL3 function redundantly in the PR-DUB complex and are essential for chromatin recruitment and transcriptional activation of associated genes.

Subunit / interactions. Core component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3, and one of MBD5 or MBD6. Distinct combinations of ASXL and MBD proteins may preferentially bind specific histone modification marks. The PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1 and OGT; KDM1B specifically associates with ASXL2 PR-DUB complexes. Interacts (via PHD domain) with MBD5 and MBD6 (via MBD domain); the interaction is probably direct and mediates association of MBD proteins with the PR-DUB core.

Subcellular location. Nucleus.

Tissue specificity. Expressed in pancreatic islets, testis, neuroblastoma, head and neck tumor.

Disease relevance. Bainbridge-Ropers syndrome (BRPS) [MIM:615485] A syndrome characterized by psychomotor retardation, feeding problems, severe postnatal growth retardation in some patients, arched eyebrows, anteverted nares, and ulnar deviation of the hands. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the Asx family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9C0F0-1	1	yes
Q9C0F0-2	2

RefSeq proteins (1): NP_085135* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007759	Asxl_HARE-HTH	Domain
IPR024811	ASX/ASX-like	Family
IPR026905	ASX-like_PHD	Domain
IPR028020	ASX_DEUBAD_dom	Domain
IPR044867	DEUBAD_dom	Domain

Pfam: PF05066, PF13919, PF13922

UniProt features (41 total): compositionally biased region 14, region of interest 12, sequence variant 5, sequence conflict 4, domain 2, splice variant 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0F0-F1	39.70	0.03

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 329 (showing top): GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, chr18q12, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOMF_SIGNALING_RECEPTOR_BINDING, GOMF_CHROMATIN_BINDING, GOCC_PCG_PROTEIN_COMPLEX, GOMF_PEROXISOME_PROLIFERATOR_ACTIVATED_RECEPTOR_BINDING, DODD_NASOPHARYNGEAL_CARCINOMA_DN, FIGUEROA_AML_METHYLATION_CLUSTER_2_DN, FIGUEROA_AML_METHYLATION_CLUSTER_5_DN

GO Biological Process (4): animal organ morphogenesis (GO:0009887), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of lipid biosynthetic process (GO:0051055), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): DNA binding (GO:0003677), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), peroxisome proliferator activated receptor binding (GO:0042975), metal ion binding (GO:0046872)

GO Cellular Component (2): PR-DUB complex (GO:0035517), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure morphogenesis	1
animal organ development	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
lipid biosynthetic process	1
negative regulation of biosynthetic process	1
negative regulation of lipid metabolic process	1
regulation of lipid biosynthetic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nucleic acid binding	1
binding	1
transition metal ion binding	1
signaling receptor binding	1
cation binding	1
PcG protein complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASXL3	EZH2	Q15910	568
ASXL3	BAP1	Q92560	561
ASXL3	ASXL2	Q76L83	554
ASXL3	BRD4	O60885	541
ASXL3	ASXL1	Q8IXJ9	521
ASXL3	NCOA1	Q15788	498
ASXL3	RNF2	Q99496	488
ASXL3	SCN2A	Q99250	469
ASXL3	NCKAP1	Q9Y2A7	463
ASXL3	WTIP	A6NIX2	461
ASXL3	CBX5	P45973	456
ASXL3	CTTNBP2	Q8WZ74	453
ASXL3	WDFY3	Q8IZQ1	448
ASXL3	DSCAM	O60469	446
ASXL3	ZBBX	A8MT70	437

IntAct

5 interactions, top by confidence:

A	B	Type	Score
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
ASXL3	TOP1	psi-mi:“MI:0915”(physical association)	0.400
ASXL3	SCD	psi-mi:“MI:0915”(physical association)	0.400
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350

BioGRID (177): ASXL3 (Biochemical Activity), BAP1 (Affinity Capture-Western), ASXL3 (Affinity Capture-Western), ASXL3 (Affinity Capture-MS), ASXL3 (Affinity Capture-MS), ASXL3 (Proximity Label-MS), ASXL3 (Proximity Label-MS), ASXL3 (Affinity Capture-MS), ASXL3 (Proximity Label-MS), ASXL3 (Affinity Capture-MS), BAP1 (Affinity Capture-Western), HCFC1 (Affinity Capture-Western), FOXK1 (Affinity Capture-Western), BRD4 (Affinity Capture-Western), ASXL3 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GTH6, A0A1D5RMD1, A2AQH4, A4FU49, A6NCI8, A6QQS3, B7ZNG4, C7EMF5, D3YU32, E9Q0C6, F5HCV3, G3X9U1, O15016, P0C671, Q32MG2, Q3V0A6, Q3V3Q4, Q4R729, Q4V7C4, Q4V8E9, Q5DTZ0, Q5H9F3, Q5SW25, Q5SWP3, Q5VV67, Q66HG9, Q68A65, Q68DN1, Q6AXV6, Q7TSG5, Q8BHW6, Q8C4A5, Q8CH19, Q8K4E0, Q8N5Q1, Q8NA61, Q8NDZ0, Q8VCF0, Q8VEG0, Q8WNU4

Diamond homologs: P59598, Q5ZM88, Q76L83, Q8BZ32, Q8C4A5, Q8IXJ9, Q9C0F0, Q9V727

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
BAP1	“up-regulates activity”	ASXL3	binding
ASXL3	“up-regulates activity”	BRD4	binding
ASXL3	“down-regulates activity”	CBX5	binding
ASXL3	“down-regulates activity”	KDM1A	binding
ASXL3	“down-regulates activity”	NR1H3	binding
ASXL3	“down-regulates activity”	THRB	binding
ASXL3	“down-regulates activity”	THR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1030 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	136
Likely pathogenic	91
Uncertain significance	406
Likely benign	220
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031441	NM_030632.3(ASXL3):c.1444del (p.Ser482fs)	Pathogenic
1031442	NM_030632.3(ASXL3):c.3049del (p.Ser1017fs)	Pathogenic
1064807	NM_030632.3(ASXL3):c.3403_3405delinsCC (p.Ser1135fs)	Pathogenic
1068542	NM_030632.3(ASXL3):c.1465G>T (p.Glu489Ter)	Pathogenic
1072421	NM_030632.3(ASXL3):c.5153del (p.Glu1718fs)	Pathogenic
1075252	NM_030632.3(ASXL3):c.3263del (p.Gly1088fs)	Pathogenic
1076372	NM_030632.3(ASXL3):c.3629C>A (p.Ser1210Ter)	Pathogenic
1174077	NM_030632.3(ASXL3):c.5819del (p.Gly1940fs)	Pathogenic
1215469	NM_030632.3(ASXL3):c.3750_3753del (p.Lys1250fs)	Pathogenic
1223193	NM_030632.3(ASXL3):c.4120_4123dup (p.Ala1375fs)	Pathogenic
1308656	NM_030632.3(ASXL3):c.3137_3144del (p.Gly1046fs)	Pathogenic
1320104	NM_030632.3(ASXL3):c.1269C>A (p.Cys423Ter)	Pathogenic
1320131	NM_030632.3(ASXL3):c.1864dup (p.Cys622fs)	Pathogenic
1320244	NM_030632.3(ASXL3):c.4899T>A (p.Tyr1633Ter)	Pathogenic
1323555	NM_030632.3(ASXL3):c.3750_3753dup (p.His1252fs)	Pathogenic
1323561	NM_030632.3(ASXL3):c.1667_1668del (p.Thr556fs)	Pathogenic
1328153	NM_030632.3(ASXL3):c.3039+1G>T	Pathogenic
1341713	NM_030632.3(ASXL3):c.4826G>A (p.Trp1609Ter)	Pathogenic
1675701	NM_030632.3(ASXL3):c.1274_1278del (p.Met425fs)	Pathogenic
1679328	NM_030632.3(ASXL3):c.3443dup (p.Pro1148_Glu1149insTer)	Pathogenic
1701334	NM_030632.3(ASXL3):c.1072_1074delinsAA (p.Tyr358fs)	Pathogenic
1701335	NM_030632.3(ASXL3):c.3745_3748delinsTTT (p.Ile1249fs)	Pathogenic
1708256	NM_030632.3(ASXL3):c.4890_4893del (p.Lys1631fs)	Pathogenic
1708662	NM_030632.3(ASXL3):c.4678C>T (p.Arg1560Ter)	Pathogenic
1709724	NM_030632.3(ASXL3):c.3275dup (p.Gly1094fs)	Pathogenic
1723054	NM_030632.3(ASXL3):c.3811_3814dup (p.Thr1272fs)	Pathogenic
1803990	NM_030632.3(ASXL3):c.1419dup (p.Pro474fs)	Pathogenic
1806649	NM_030632.3(ASXL3):c.1897_1898del (p.Gln633fs)	Pathogenic
1807800	GRCh37/hg19 18q12.1(chr18:30988810-31359711)x1	Pathogenic
2051555	NM_030632.3(ASXL3):c.1378dup (p.Thr460fs)	Pathogenic

SpliceAI

2550 predictions. Top by Δscore:

Variant	Effect	Δscore
18:33578681:GCCTG:G	donor_gain	1.0000
18:33578682:CCTGG:C	donor_loss	1.0000
18:33578684:TGG:T	donor_loss	1.0000
18:33578685:GGT:G	donor_loss	1.0000
18:33578686:G:GC	donor_loss	1.0000
18:33578686:G:GG	donor_gain	1.0000
18:33607674:AAGGT:A	donor_loss	1.0000
18:33607675:AGGT:A	donor_loss	1.0000
18:33607676:GGTC:G	donor_loss	1.0000
18:33607677:G:C	donor_loss	1.0000
18:33607678:T:A	donor_loss	1.0000
18:33621735:T:G	donor_gain	1.0000
18:33621735:T:TG	donor_gain	1.0000
18:33641783:A:G	acceptor_gain	1.0000
18:33644892:A:AG	acceptor_gain	1.0000
18:33644892:AGT:A	acceptor_gain	1.0000
18:33644893:G:GA	acceptor_gain	1.0000
18:33644893:GTG:G	acceptor_gain	1.0000
18:33645003:G:GG	donor_gain	1.0000
18:33645656:GAA:G	donor_gain	1.0000
18:33645658:A:AG	donor_gain	1.0000
18:33646233:A:AG	acceptor_gain	1.0000
18:33646234:A:G	acceptor_gain	1.0000
18:33646349:TGGAG:T	donor_gain	1.0000
18:33646350:GGAG:G	donor_gain	1.0000
18:33646350:GGAGG:G	donor_gain	1.0000
18:33646351:GAG:G	donor_gain	1.0000
18:33646351:GAGG:G	donor_gain	1.0000
18:33646352:AG:A	donor_gain	1.0000
18:33646353:GG:G	donor_gain	1.0000

AlphaMissense

14706 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:33578665:T:A	W12R	1.000
18:33578665:T:C	W12R	1.000
18:33578667:G:C	W12C	1.000
18:33578667:G:T	W12C	1.000
18:33578678:C:A	A16D	1.000
18:33607637:T:A	I33K	1.000
18:33607637:T:G	I33R	1.000
18:33607649:T:A	I37N	1.000
18:33644917:T:C	L54P	1.000
18:33644929:T:C	L58P	1.000
18:33670740:T:A	V182D	1.000
18:33670746:T:C	L184S	1.000
18:33683455:T:C	S256P	1.000
18:33683459:T:A	I257N	1.000
18:33683459:T:G	I257S	1.000
18:33683462:T:C	L258P	1.000
18:33683477:T:C	L263S	1.000
18:33683480:G:T	R264M	1.000
18:33683486:T:C	L266S	1.000
18:33683537:T:C	L283P	1.000
18:33683549:T:C	L287P	1.000
18:33732019:T:C	F311L	1.000
18:33732021:C:A	F311L	1.000
18:33732021:C:G	F311L	1.000
18:33732043:T:A	W319R	1.000
18:33732043:T:C	W319R	1.000
18:33732044:G:C	W319S	1.000
18:33732045:G:C	W319C	1.000
18:33732045:G:T	W319C	1.000
18:33732056:T:C	L323P	1.000

dbSNP variants (sampled 300 via entrez): RS1000015868 (18:33676812 ACCCT>A), RS1000052013 (18:33596729 G>A,C), RS1000056869 (18:33712994 C>T), RS1000058051 (18:33748304 A>G,T), RS1000063252 (18:33726007 T>G), RS1000086636 (18:33677168 T>A), RS1000091618 (18:33590865 G>A,T), RS1000102319 (18:33576417 C>T), RS1000108637 (18:33748113 C>T), RS1000109659 (18:33619865 G>T), RS1000148144 (18:33703730 A>C), RS1000262693 (18:33613301 T>A), RS1000273503 (18:33701128 A>G), RS1000282286 (18:33658737 A>T), RS1000299018 (18:33589270 A>C,G)

Disease associations

OMIM: gene MIM:615115 | disease phenotypes: MIM:615485, MIM:614429

GenCC curated gene-disease

Disease	Classification	Inheritance
severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (10): severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome (MONDO:0014205), neurodevelopmental disorder (MONDO:0700092), syndromic intellectual disability (MONDO:0000508), hereditary ataxia (MONDO:0100309), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), vascular disorder (MONDO:0005385), cleft palate (MONDO:0016064), ventricular septal defect (MONDO:0002070), strabismus (MONDO:0003432)

Orphanet (8): Bainbridge-Ropers syndrome (Orphanet:352577), Rare genetic syndromic intellectual disability (Orphanet:183763), Hereditary ataxia (Orphanet:183518), Rare syndromic intellectual disability (Orphanet:102369), Cleft palate (Orphanet:2014), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

107 total (30 of 107 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000154	Wide mouth
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000239	Large fontanelles
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000331	Short chin
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000452	Choanal stenosis
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002113_6	Pulmonary function	7.000000e-06
GCST002875_25	Diisocyanate-induced asthma	7.000000e-06
GCST002875_51	Diisocyanate-induced asthma	5.000000e-06
GCST003783_16	Multiple system atrophy (pathologically confirmed)	7.000000e-06
GCST006627_46	Diastolic blood pressure	2.000000e-11
GCST006940_110	Neurociticism	3.000000e-10
GCST007267_20	Systolic blood pressure	6.000000e-12
GCST008759_24	Intake of total sugars	9.000000e-06
GCST009325_61	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-08
GCST010988_74	Adult body size	3.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004312	vital capacity
EFO:0006995	response to diisocyanate
EFO:0006336	diastolic blood pressure
EFO:0007660	neuroticism measurement
EFO:0006335	systolic blood pressure
EFO:0010158	sugar consumption measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D013285	Strabismus	C10.292.562.887; C11.590.810
D014652	Vascular Diseases	C14.907
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, affects cotreatment, increases expression	8
trichostatin A	affects cotreatment, increases expression	3
entinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
bisphenol A	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Oxygen	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental 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