WASF1

protein-coding

WASP family member 1, the group of Wiskott-Aldrich Syndrome protein family|A-kinase anchoring proteins|SCAR/WAVE complex

Gene summary

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]

MANE transcript

NM_003931.3

Inheritance

ClinVar variants

P:13U:106B:30

Top phenotype

Neurodevelopmental disorder with absent language and variable seizures

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr6:110,099,819-110,180,004

External References & Databases

Ensembl (ENSG00000112290)

Transcript & Mutation Effects

hg38 • Region Span ~80.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with absent language and variable seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032876

Submitter: G2P

neurodevelopmental disorder with absent language and variable seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032876

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorder with absent language and variable seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032876

Submitter: Ambry Genetics

neurodevelopmental disorder with absent language and variable seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032876

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with absent language and variable seizuresAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29961568

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WASF1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 66

Inborn genetic diseasesTotal: 46

not specifiedTotal: 27

Neurodevelopmental disorder with absent language and variable seizuresTotal: 22

WASF1-related disorderTotal: 17

Intellectual disabilityTotal: 4

Epileptic encephalopathyTotal: 1

Hereditary ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003931.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	14 clinvar		16
missense	1 clinvar	2 clinvar	95 clinvar	16 clinvar		114
nonsense	3 clinvar	1 clinvar	2 clinvar			6
start loss			1 clinvar			1
frameshift	3 clinvar	3 clinvar	3 clinvar			9
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	7	6	106	30	0	149

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003931.3	RefSeq	NP_003922.1	8	MANE Select
ENST00000392589.6	Ensembl	ENSP00000376368.1	8	MANE Select
NM_001024934.2	RefSeq	NP_001020105.1	8	Standard
NM_001024935.2	RefSeq	NP_001020106.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
Choline metabolism in cancer - Homo sapiens (human)
Adherens junction - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

receptor-mediated endocytosis
Rac protein signal transduction
actin filament polymerization
positive regulation of neurotrophin TRK receptor signaling pathway
protein-containing complex assembly

Molecular Function

actin binding
protein binding
Rac GTPase binding
protein kinase A binding

Cellular Component

mitochondrial outer membrane
cytoskeleton
focal adhesion
actin cytoskeleton
lamellipodium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392589
Coding exons: 8
Length: 80186
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.55	175	299	0.586	0.0000158	3582
Missense (PolyPhen)		14	44.693	0.31325		504
Synonymous	1.32	88	105	0.836	0.00000545	1186
Loss of Function	4.15	1	22.1	0.0453	0.00000126	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex (By similarity). As component of the WAVE1 complex, required for BDNF- NTRK2 endocytic trafficking and signaling from early endosomes (By similarity). {ECO:0000250|UniProtKB:Q8R5H6, ECO:0000269|PubMed:9889097}.;

Intolerance Scores

LoFtool: 0.317
RVIS EVS: -0.05
RVIS percentile EVS: 50.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.923

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium