WAC

Chr 10AD

WW domain containing adaptor with coiled-coil

Also known as: BM-016, DESSH, PRO1741, Wwp4

NCBI Gene: 51322 ENSG00000095787 UniProt: Q9BTA9 OMIM: 615049

The WAC protein contains a WW domain that mediates protein-protein interactions by binding proline-rich peptide motifs and localizes to nuclear speckles. Loss-of-function mutations cause Desanto-Shinawi syndrome, an autosomal dominant neurodevelopmental disorder. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, Dec 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.081 OMIM phenotype

Clinical Summary— WAC

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Gene-Disease Validity (ClinGen)

DeSanto-Shinawi syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

116 unique Pathogenic / Likely Pathogenic· 159 VUS of 436 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — WAC

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.08LOEUF

pLI 1.000

Z-score 5.53

OE 0.00 (0.00–0.08)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.51Z-score

OE missense 0.77 (0.69–0.85)

262 obs / 340.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.08)

0≤0.351.4

Missense OE?0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 0 / 35.6Missense obs/exp: 262 / 340.5Syn Z: -0.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveWAC-related Desanto-Shinawi syndromeLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.1799th %ile

LOF

0.90top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 100% of P/LP variants are LoF · LOEUF 0.08 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFThe clinical features associated with WAC haploinsufficiency include recognizable dysmorphic facial features that were recently delineated as DeSanto-Shinawi syndrome (DESSH; OMIM 616708).1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29928181 ↗

ClinVar Variant Classifications

436 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic84

Likely Pathogenic32

VUS159

Likely Benign76

Benign44

Conflicting10

Pathogenic

Likely Pathogenic

159

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	84	0	0	0	84
Likely Pathogenic	32	0	0	0	32
VUS	5	140	11	3	159
Likely Benign	0	26	33	17	76
Benign	0	5	36	3	44
Conflicting	—				10
Total	121	171	80	23	405

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap WAC — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →