WASF1

Chr 6AD

WASP family member 1

Also known as: NEDALVS, SCAR1, WAVE, WAVE-1, WAVE1

NCBI Gene: 8936 ENSG00000112290 UniProt: Q92558 OMIM: 605035

This protein regulates actin cytoskeleton dynamics by promoting actin filament formation as part of the WAVE complex and is involved in BDNF-NTRK2 endocytic trafficking and mitochondrial dynamics. Mutations cause neurodevelopmental disorder with absent language and variable seizures with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.998, LOEUF 0.215), indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene, a member of the Wiskott-Aldrich syndrome protein (WASP)-family, plays a critical role downstream of Rac, a Rho-family small GTPase, in regulating the actin cytoskeleton required for membrane ruffling. It has been shown to associate with an actin nucleation core Arp2/3 complex while enhancing actin polymerization in vitro. Wiskott-Aldrich syndrome is a disease of the immune system, likely due to defects in regulation of actin cytoskeleton. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with absent language and variable seizuresMIM #618707

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neurodevelopmental disorder with absent language and variable seizures; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.21

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.998

Z-score 4.15

OE 0.05 (0.01–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.55Z-score

OE missense 0.59 (0.52–0.66)

175 obs / 298.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.01–0.21)

0≤0.351.4

Missense OE?0.59 (0.52–0.66)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 1 / 22.1Missense obs/exp: 175 / 298.9Syn Z: 1.32

Background carrier burden — how many people carry a rare variant somewhere in WASF1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

511 rare PASS variants

Rare truncating (LoF)

1 in 42,000

17 rare PASS variants

Rare synonymous (reference)

1 in 330

216 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for WASF1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 55,000
South Asian	~43k	1 in 150	≈ 1 in 18,000
Remaining (unassigned)	~30k	1 in 150	none seen
European (Finnish)	~27k	1 in 340	none seen
Admixed American	~22k	1 in 190	≈ 1 in 6,700
African / African American	~21k	1 in 210	≈ 1 in 15,000
East Asian	~20k	1 in 140	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 550	none seen
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓