WAC

Summary

WAC (WW domain containing adaptor with coiled-coil, HGNC:17327) is a protein-coding gene on chromosome 10p12.1, encoding WW domain-containing adapter protein with coiled-coil (Q9BTA9). Acts as a linker between gene transcription and histone H2B monoubiquitination at ‘Lys-120’ (H2BK120ub1). It is a selective cancer dependency (DepMap: 32.1% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene contains a WW domain, which is a protein module found in a wide range of signaling proteins. This domain mediates protein-protein interactions and binds proteins containing short linear peptide motifs that are proline-rich or contain at least one proline. This gene product shares 94% sequence identity with the WAC protein in mouse, however, its exact function is not known. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51322 — RefSeq curated summary.

At a glance

• Gene–disease (curated): DeSanto-Shinawi syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 409 total — 84 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 104
• Cancer dependency (DepMap): dependent in 32.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_016628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17327
Approved symbol	WAC
Name	WW domain containing adaptor with coiled-coil
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Aliases	Wwp4, FLJ31290, PRO1741, BM-016, MGC10753
Ensembl gene	ENSG00000095787
Ensembl biotype	protein_coding
OMIM	615049
Entrez	51322

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 27 protein_coding, 8 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000345541, ENST00000347934, ENST00000354911, ENST00000375646, ENST00000375664, ENST00000414108, ENST00000420266, ENST00000424454, ENST00000428935, ENST00000439676, ENST00000442148, ENST00000448193, ENST00000472862, ENST00000480474, ENST00000495268, ENST00000526722, ENST00000528491, ENST00000530865, ENST00000628285, ENST00000651441, ENST00000651598, ENST00000651885, ENST00000679398, ENST00000679428, ENST00000679570, ENST00000680735, ENST00000681112, ENST00000700325, ENST00000706612, ENST00000910892, ENST00000910895, ENST00000910896, ENST00000910897, ENST00000910899, ENST00000910902, ENST00000910903, ENST00000923554, ENST00000923555, ENST00000923556, ENST00000923557

RefSeq mRNA: 3 — MANE Select: NM_016628 NM_016628, NM_100264, NM_100486

CCDS: CCDS7159, CCDS7160, CCDS7161

Canonical transcript exons

ENST00000354911 — 14 exons

Exon	Start	End
ENSE00001789754	28619537	28623112
ENSE00003474191	28616173	28616362
ENSE00003494233	28608186	28608431
ENSE00003503690	28610699	28610821
ENSE00003564485	28595733	28596041
ENSE00003612477	28614567	28614685
ENSE00003621128	28617657	28617784
ENSE00003677321	28611774	28611922
ENSE00003723380	28589736	28589851
ENSE00003724724	28583399	28583505
ENSE00003726405	28590720	28590832
ENSE00003996317	28533118	28533620
ENSE00003996318	28533998	28534034
ENSE00003996319	28535562	28535757

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.6202 / max 1308.9833, expressed in 1824 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104485	30.7251	1818
104482	12.0345	1769
104500	1.5262	853
104487	1.4450	927
104484	0.9684	617
104486	0.9663	559
104490	0.6829	287
104489	0.6086	357
104493	0.5065	236
104488	0.4593	231

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.78	gold quality
secondary oocyte	CL:0000655	99.51	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.26	gold quality
germinal epithelium of ovary	UBERON:0001304	99.10	gold quality
caput epididymis	UBERON:0004358	99.05	gold quality
cauda epididymis	UBERON:0004360	98.94	gold quality
corpus epididymis	UBERON:0004359	98.91	gold quality
parietal pleura	UBERON:0002400	98.75	gold quality
superficial temporal artery	UBERON:0001614	98.74	gold quality
amniotic fluid	UBERON:0000173	98.70	gold quality
trabecular bone tissue	UBERON:0002483	98.69	gold quality
calcaneal tendon	UBERON:0003701	98.69	gold quality
visceral pleura	UBERON:0002401	98.67	gold quality
medial globus pallidus	UBERON:0002477	98.56	gold quality
pleura	UBERON:0000977	98.54	gold quality
globus pallidus	UBERON:0001875	98.54	gold quality
pigmented layer of retina	UBERON:0001782	98.45	gold quality
skin of hip	UBERON:0001554	98.44	gold quality
pons	UBERON:0000988	98.42	gold quality
palpebral conjunctiva	UBERON:0001812	98.34	gold quality
inferior vagus X ganglion	UBERON:0005363	98.33	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.31	gold quality
upper leg skin	UBERON:0004262	98.30	gold quality
tibia	UBERON:0000979	98.28	gold quality
pylorus	UBERON:0001166	98.28	gold quality
lateral globus pallidus	UBERON:0002476	98.27	gold quality
gingival epithelium	UBERON:0001949	98.23	gold quality
subthalamic nucleus	UBERON:0001906	98.19	gold quality
mammary duct	UBERON:0001765	98.17	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.17	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

206 targeting WAC, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-507	99.97	70.11	1915

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 32.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• The identification of SCOC and WAC as novel regulatory proteins with diverse functions in autophagy contributes towards a fuller understanding of autophagosome formation. (PMID:22354037)
• WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome (PMID:26264232)
• Data show that WAC directly binds to GM130 and that this binding is required for autophagosome formation through interacting with GABARAP regulating its subcellular localization. (PMID:26687599)
• De novo WAC loss-of-function mutations were identified through exome sequencing of individuals with unexplained intellectual disability. (PMID:26757981)
• Our observation allows us to redefine the smallest region of overlap among patients reported so far, with a size of 80 Kb and which contains only the WAC gene. These findings strengthen the hypothesis that haploinsufficency of WAC gene might be likely responsible for intellectual disability and behavior disorders. (PMID:27119754)
• these results indicate an important role for WAC in promoting Plk1 activation and the timely entry into mitosis. (PMID:30021153)
• A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES). (PMID:32214004)
• Self-limited focal epilepsy and childhood apraxia of speech with WAC pathogenic variants. (PMID:33387902)
• Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript. (PMID:33857290)
• WAC, a novel GBM tumor suppressor, induces GBM cell apoptosis and promotes autophagy. (PMID:34581882)
• Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant. (PMID:35018708)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	waca	ENSDARG00000012577
mus_musculus	Wac	ENSMUSG00000024283
rattus_norvegicus	Wac	ENSRNOG00000018698
drosophila_melanogaster	wcy	FBGN0030812
caenorhabditis_elegans	wac-1.2	WBGENE00012732

Protein

Protein identifiers

WW domain-containing adapter protein with coiled-coil — Q9BTA9 (reviewed: Q9BTA9)

All UniProt accessions (19): Q9BTA9, A0A0A0MRT2, A0A0A0MSR1, A0A0D9SFY7, A0A494C0B7, A0A494C0C1, A0A494C0S5, A0A7P0T961, A0A7P0TBE3, A0A7P0Z479, A0A8V8TQV5, A0A8V8TR65, A0A9L9PXQ9, C9JD58, C9JMU2, C9JVK6, E9PMZ7, J3QT76, J3QTA0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a linker between gene transcription and histone H2B monoubiquitination at ‘Lys-120’ (H2BK120ub1). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription. Regulates the cell-cycle checkpoint activation in response to DNA damage. Positive regulator of amino acid starvation-induced autophagy. Also acts as a negative regulator of basal autophagy. Positively regulates MTOR activity by promoting, in an energy-dependent manner, the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex. This leads to the dimerization of the mTORC1 complex and its subsequent activation. May negatively regulate the ubiquitin proteasome pathway.

Subunit / interactions. Interacts (via coiled coil domain) with RNF20, RNF40 and UBE2A. Interacts (via WW domain) with RNA polymerase II. Interacts with MTOR and other components of the MTOR pathway including RPTOR, RUVBL1, RUVBL2, TTI1 and TTI2.

Subcellular location. Nucleus speckle. Nucleus.

Post-translational modifications. Phosphorylated on tyrosine residues.

Disease relevance. DeSanto-Shinawi syndrome (DESSH) [MIM:616708] An autosomal dominant syndrome characterized by developmental delay, hypotonia, behavioral problems, eye abnormalities, constipation, feeding difficulties, seizures and sleep problems. Patients exhibit dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Additional variable features are posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies. The disease is caused by variants affecting the gene represented in this entry. Defects in WAC are the cause of a form of intellectual disability characterized by hypotonia, behavioral problems and distinctive facial dysmorphisms including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin.

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

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BTA9-1	1	yes
Q9BTA9-2	2
Q9BTA9-3	3
Q9BTA9-5	4

RefSeq proteins (3): NP_057712, NP_567822, NP_567823 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001202	WW_dom	Domain
IPR036020	WW_dom_sf	Homologous_superfamily
IPR038867	WAC	Family

Pfam: PF00397

UniProt features (44 total): compositionally biased region 15, modified residue 11, sequence variant 5, splice variant 4, region of interest 3, sequence conflict 3, chain 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTA9-F1	55.71	0.14

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 (11): 53, 131, 142, 225, 293, 302, 446, 471, 511, 523, 525

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins

MSigDB gene sets: 453 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, CMYB_01, AAGCCAT_MIR135A_MIR135B, GOBP_CELL_CYCLE_PHASE_TRANSITION, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROAUTOPHAGY

GO Biological Process (9): chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), regulation of autophagy (GO:0010506), positive regulation of macroautophagy (GO:0016239), mitotic G1 DNA damage checkpoint signaling (GO:0031571), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of TORC1 signaling (GO:1904263), chromatin organization (GO:0006325)

GO Molecular Function (3): RNA polymerase II complex binding (GO:0000993), chromatin binding (GO:0003682), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein ubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
chromatin organization	1
cellular response to stress	1
autophagy	1
regulation of catabolic process	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
cellular component organization	1
RNA polymerase core enzyme binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1694 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WAC	RNF40	O75150	684
WAC	RNF20	Q5VTR2	682
WAC	SCOC	Q9UIL1	663
WAC	SMAD4	Q13485	496
WAC	UVRAG	Q9P2Y5	482
WAC	CNEP1R1	Q8N9A8	473
WAC	MORN1	Q5T089	463
WAC	C6orf52	Q5T4I8	431
WAC	BRINP1	O60477	423
WAC	DAZAP1	Q96EP5	413
WAC	ZCCHC7	Q8N3Z6	413
WAC	PTPRK	Q15262	401
WAC	TRIM31	Q9BZY9	398
WAC	ZBTB20	Q9HC78	390
WAC	SP2	Q02086	385

IntAct

85 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
RNF40	RNF20	psi-mi:“MI:0914”(association)	0.820
KRT15	WAC	psi-mi:“MI:0915”(physical association)	0.670
WAC	KRT15	psi-mi:“MI:0915”(physical association)	0.670
KLC3	WAC	psi-mi:“MI:0915”(physical association)	0.560
SYTL5	WAC	psi-mi:“MI:0915”(physical association)	0.560
WAC	AKAP9	psi-mi:“MI:0915”(physical association)	0.560
WAC		psi-mi:“MI:0915”(physical association)	0.560
TRAF1	WAC	psi-mi:“MI:0915”(physical association)	0.560
WAC	NFE2L2	psi-mi:“MI:0915”(physical association)	0.560
WAC	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
WAC	DYDC1	psi-mi:“MI:0915”(physical association)	0.560
WAC	TRAF3IP3	psi-mi:“MI:0915”(physical association)	0.560
WAC	SYTL5	psi-mi:“MI:0915”(physical association)	0.560
DYDC1	WAC	psi-mi:“MI:0915”(physical association)	0.560
TRAF3IP3	WAC	psi-mi:“MI:0915”(physical association)	0.560
WAC	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
NFE2L2	WAC	psi-mi:“MI:0915”(physical association)	0.560
WAC	KLC3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (144): WAC (Two-hybrid), WAC (Two-hybrid), WAC (Two-hybrid), WAC (Two-hybrid), WAC (Two-hybrid), WAC (Two-hybrid), TRAF3IP3 (Two-hybrid), SYTL5 (Two-hybrid), DYDC1 (Two-hybrid), KLC3 (Two-hybrid), WAC (Two-hybrid), WAC (Affinity Capture-Western), WAC (Affinity Capture-MS), WAC (Two-hybrid), WAC (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: B6EUA9, F4JCC1, O14776, Q3B807, Q5U4Q0, Q7ZUK7, Q8CGF7, Q924H7, Q9BTA9, Q9VX88

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CDK1	“up-regulates activity”	WAC	phosphorylation
WAC	“up-regulates activity”	PLK1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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
mRNA Polyadenylation	5	11.3×	6e-03
Processing of Capped Intron-Containing Pre-mRNA	5	10.5×	6e-03
mRNA Splicing - Major Pathway	7	9.8×	2e-03
Dengue Virus-Host Interactions	7	8.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	84
Likely pathogenic	25
Uncertain significance	146
Likely benign	67
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030572	NM_016628.5(WAC):c.1101dup (p.Pro368fs)	Pathogenic
1072110	NM_016628.5(WAC):c.444C>A (p.Tyr148Ter)	Pathogenic
1072462	NM_016628.5(WAC):c.1072del (p.Gln358fs)	Pathogenic
1098366	NM_016628.5(WAC):c.1303C>T (p.Gln435Ter)	Pathogenic
1098396	NM_016628.5(WAC):c.1438-1G>T	Pathogenic
1179573	NM_016628.5(WAC):c.255_256del (p.Arg85fs)	Pathogenic
1184964	NM_016628.5(WAC):c.1567dup (p.Ser523fs)	Pathogenic
1203538	NM_016628.5(WAC):c.1319_1337dup (p.Ser446_Pro447insAsnIleTer)	Pathogenic
1210712	NM_016628.5(WAC):c.1747-1G>A	Pathogenic
1323759	NM_016628.5(WAC):c.1233del (p.Ser412fs)	Pathogenic
1343214	NM_016628.5(WAC):c.29_30del (p.Arg10fs)	Pathogenic
1679352	NM_016628.5(WAC):c.1503dup (p.Asp502Ter)	Pathogenic
1698975	NM_016628.5(WAC):c.1631dup (p.Gln545fs)	Pathogenic
1700140	NM_016628.5(WAC):c.1746+2T>C	Pathogenic
1710204	NM_016628.5(WAC):c.207C>A (p.Tyr69Ter)	Pathogenic
1712694	NM_016628.5(WAC):c.228_231del (p.Ser76fs)	Pathogenic
1727053	NM_016628.5(WAC):c.1830_1833dup (p.Val612fs)	Pathogenic
1727239	NM_016628.5(WAC):c.464dup (p.Gln156fs)	Pathogenic
219139	NM_016628.5(WAC):c.263_266del (p.Glu88fs)	Pathogenic
219140	NM_016628.5(WAC):c.1721G>A (p.Trp574Ter)	Pathogenic
219141	NM_016628.5(WAC):c.267_268dup (p.Asp90fs)	Pathogenic
219142	NM_016628.5(WAC):c.374C>A (p.Ser125Ter)	Pathogenic
219143	NM_016628.5(WAC):c.1852C>T (p.Gln618Ter)	Pathogenic
219144	NM_016628.5(WAC):c.112del (p.Ser38fs)	Pathogenic
2266122	NM_016628.5(WAC):c.305dup (p.His102fs)	Pathogenic
2412806	NM_016628.5(WAC):c.1788del (p.His597fs)	Pathogenic
2438660	NM_016628.5(WAC):c.265_266del (p.Arg89fs)	Pathogenic
2501366	NM_016628.5(WAC):c.350dup (p.Ser118fs)	Pathogenic
2577830	NM_016628.5(WAC):c.1864dup (p.Arg622fs)	Pathogenic
2627832	NM_016628.5(WAC):c.485_486del (p.Glu162fs)	Pathogenic

SpliceAI

2510 predictions. Top by Δscore:

Variant	Effect	Δscore
10:28534031:CCAG:C	donor_loss	1.0000
10:28534032:CAGG:C	donor_loss	1.0000
10:28534033:AGG:A	donor_loss	1.0000
10:28534035:GT:G	donor_loss	1.0000
10:28534036:T:A	donor_loss	1.0000
10:28535541:T:A	acceptor_gain	1.0000
10:28535542:G:A	acceptor_gain	1.0000
10:28535560:A:AG	acceptor_gain	1.0000
10:28535561:G:GA	acceptor_gain	1.0000
10:28535710:G:GG	donor_gain	1.0000
10:28583394:TTAA:T	acceptor_loss	1.0000
10:28583395:TAAG:T	acceptor_loss	1.0000
10:28583396:A:AG	acceptor_gain	1.0000
10:28583396:AAG:A	acceptor_gain	1.0000
10:28583396:AAGG:A	acceptor_gain	1.0000
10:28583397:A:AG	acceptor_gain	1.0000
10:28583397:AG:A	acceptor_gain	1.0000
10:28583398:G:A	acceptor_gain	1.0000
10:28583398:G:GG	acceptor_gain	1.0000
10:28583501:ATGCA:A	donor_gain	1.0000
10:28583502:TGCA:T	donor_gain	1.0000
10:28583503:GCA:G	donor_gain	1.0000
10:28583503:GCAG:G	donor_gain	1.0000
10:28583504:CA:C	donor_gain	1.0000
10:28583504:CAGT:C	donor_loss	1.0000
10:28583505:AGTAA:A	donor_loss	1.0000
10:28583506:G:GG	donor_gain	1.0000
10:28583506:GTAAG:G	donor_loss	1.0000
10:28583507:TAA:T	donor_loss	1.0000
10:28583508:AA:A	donor_loss	1.0000

AlphaMissense

4221 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:28589757:T:A	W135R	1.000
10:28589757:T:C	W135R	1.000
10:28589758:G:C	W135S	1.000
10:28589759:G:C	W135C	1.000
10:28589759:G:T	W135C	1.000
10:28589760:T:C	S136P	1.000
10:28589766:C:G	H138D	1.000
10:28589767:A:C	H138P	1.000
10:28589772:A:C	S140R	1.000
10:28589773:G:A	S140N	1.000
10:28589773:G:T	S140I	1.000
10:28589774:C:A	S140R	1.000
10:28589774:C:G	S140R	1.000
10:28589776:C:T	S141F	1.000
10:28589781:G:T	G143W	1.000
10:28589782:G:A	G143E	1.000
10:28589782:G:T	G143V	1.000
10:28589784:A:G	K144E	1.000
10:28589785:A:T	K144I	1.000
10:28589786:A:C	K144N	1.000
10:28589786:A:T	K144N	1.000
10:28589790:T:A	Y146N	1.000
10:28589790:T:C	Y146H	1.000
10:28589790:T:G	Y146D	1.000
10:28589791:A:C	Y146S	1.000
10:28589791:A:G	Y146C	1.000
10:28589793:T:A	Y147N	1.000
10:28589793:T:C	Y147H	1.000
10:28589793:T:G	Y147D	1.000
10:28589796:T:A	Y148N	1.000

dbSNP variants (sampled 300 via entrez): RS1000028776 (10:28599938 T>C,G), RS1000030701 (10:28585845 T>C,G), RS1000080134 (10:28590036 C>G,T), RS1000125422 (10:28605762 A>T), RS1000144733 (10:28553632 T>A,G), RS1000156021 (10:28602303 ACTTT>A), RS1000180830 (10:28538518 G>A), RS1000245558 (10:28559047 T>A), RS1000277218 (10:28543741 A>G), RS1000316245 (10:28622392 T>C), RS1000319614 (10:28558864 G>A), RS1000320258 (10:28584820 G>A), RS1000323133 (10:28582034 T>G), RS1000324234 (10:28587893 A>G), RS1000363980 (10:28607897 G>A)

Disease associations

OMIM: gene MIM:615049 | disease phenotypes: MIM:616708, MIM:260400

GenCC curated gene-disease

Disease	Classification	Inheritance
DeSanto-Shinawi syndrome due to WAC point mutation	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
DeSanto-Shinawi syndrome	Definitive	AD

Mondo (5): DeSanto-Shinawi syndrome due to WAC point mutation (MONDO:0014741), DeSanto-Shinawi syndrome (MONDO:0018760), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), Shwachman-Diamond syndrome (MONDO:0009833)

Orphanet (6): Facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to 10p11.21p12.31 microdeletion (Orphanet:284169), Facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to WAC point mutation (Orphanet:466950), WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome (Orphanet:466943), Rare genetic intellectual disability (Orphanet:183757), Shwachman-Diamond syndrome (Orphanet:811), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

104 total (30 of 104 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000125	Pelvic kidney
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000321	Square face
HP:0000337	Broad forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000395	Prominent antihelix
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia
HP:0000455	Broad nasal tip
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000539	Abnormality of refraction
HP:0000540	Hypermetropia
HP:0000545	Myopia

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004483_6	Multiple myeloma	2.000000e-08
GCST005580_319	Intraocular pressure	6.000000e-09
GCST006627_14	Diastolic blood pressure	2.000000e-10
GCST90002392_608	Mean corpuscular volume	2.000000e-09
GCST90002396_480	Mean reticulocyte volume	1.000000e-15
GCST90002397_707	Mean spheric corpuscular volume	1.000000e-09
GCST90013406_109	Liver enzyme levels (alkaline phosphatase)	4.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0010701	mean reticulocyte volume
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, increases methylation, affects cotreatment	8
trichostatin A	affects cotreatment, decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
bisphenol A	affects expression, decreases methylation	2
arsenite	increases methylation, affects binding, decreases reaction	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Caffeine	affects phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Phenobarbital	affects expression	1
Thiram	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E4KU	ICC24	Cancer cell line	Female

Clinical trials (associated diseases)

203 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,
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06807723	Not specified	RECRUITING	Further Delineation of the De Santo Shinawi Syndrome Phenotype Using a Series of Individuals Carrying a Pathogenic Variant of the WAC Gene
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge