WAS

protein-coding

WASP actin nucleation promoting factor, the group of Wiskott-Aldrich Syndrome protein family

Gene summary

The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known. [provided by RefSeq, Jul 2008]

Previous symbols:

IMD2
THC

MANE transcript

NM_000377.3

Inheritance

XL, AD, XLR

ClinVar variants

P:214U:216B:211

Top phenotype

Wiskott-Aldrich syndrome; Thrombocytopenia 1; Neutropenia, severe congenital, X-linked

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:48,676,596-48,691,431

External References & Databases

Ensembl (ENSG00000015285)

Transcript & Mutation Effects

hg38 • Region Span ~14.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombocytopenia 1SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010743

Submitter: Orphanet

Wiskott-Aldrich syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010518

Submitter: Orphanet

Wiskott-Aldrich syndromeDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010518

Submitter: Natera

X-linked severe congenital neutropeniaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010294

Submitter: Labcorp Genetics (formerly Invitae)

Wiskott-Aldrich syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010518

Submitter: Labcorp Genetics (formerly Invitae)

X-linked severe congenital neutropeniaDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010294

Submitter: Natera

Wiskott-Aldrich syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010518

Submitter: PanelApp Australia

X-linked severe congenital neutropeniaSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010294

Submitter: Orphanet

X-linked severe congenital neutropeniaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010294

Submitter: PanelApp Australia

thrombocytopenia 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010743

Submitter: PanelApp Australia

Wiskott-Aldrich syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010518

Submitter: Ambry Genetics

X-linked severe congenital neutropeniaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010294

Submitter: ClinGen

WAS was first reported in relation to X-linked recessive severe congenital neutropenia in 2001 (Devriendt K, et al., 2001, PMID: 11242115). Severe congenital neutropenia is typically characterized by severe neutropenia, recurrent bacterial infections, and a maturation arrest at the promyelocyte/myelocyte stage in the bone marrow. Of note, WAS is also reported in relation to Wiskott-Aldrich syndrome and X-linked thrombocytopenia, diseases with different phenotypes characterized by platelet defects such as thrombocytopenia and small platelets, and in Wiskott-Aldrich syndrome this is accompanied by eczema and variable immunodeficiency caused by diminished lymphocyte function and numbers. Neutrophil counts, however, are normal in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. All Wiskott-Aldrich syndrome and X-linked thrombocytopenia mutations in WAS characterized so far result in partial or complete loss of WASP function, whereas those related to neutropenia are gain of function, resulting from lost autoinhibitory regulation of WASP with consequent enhanced activation. Thus, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism and phenotypic variability, and WAS related X-linked recessive severe congenital neutropenia is considered a distinct disease entity while Wiskott-Aldrich syndrome and X-linked thrombocytopenia are considered a lumped entity along a continuum of disease. The curation for Wiskott-Aldrich syndrome (including X-linked thrombocytopenia) has been curated separately by the Hereditary Cancer GCEP. The curation of WAS related X-linked recessive severe congenital neutropenia includes both case-level and experimental evidence. Six missense variants, in the GTPase-binding domain, have been reported in 11 probands, and 11 additional affected family members, in eight publications (PMIDs: 11242115, 16804117, 19006568, 28956125, 29991546, 31352750, 31732620, 34384840). Experimental evidence includes expression of WAS in relevant tissues of lymphocytes, spleen and thymus (PMID: 8069912) and the biochemical function of WAS in actin filament polymerization (PMID: 8625410), consistent with the increased actin polymerization observed in both patient (PMID: 16804117, 30124469) and non-patient (PMID: 11242115) cells harboring these gain of function mutations. Additionally, transgenic zebrafish (PMID: 23868979) and knockin mouse models recapitulate the hyperactive neutrophils observed in patients (PMID: 30124469). In summary, WAS is definitively associated with X-linked recessive severe congenital neutropenia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date of 11/18/2021 (SOPv8).

Wiskott-Aldrich syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010518

Submitter: ClinGen

There is abundant published evidence associating the WAS gene with Wiskott-Aldrich syndrome since the gene-disease relationship was first proposed by Derry et al. (1994). Multiple case level studies have been performed with WAS patients that have variants in the WAS gene. WAS expresses in lymphocytes, spleen and thymus. Northern blot and Western blot analysis for WAS indicated no expression of RNA or protein from B lymphoblasts derived from peripheral blood of WAS patients. Multiple WAS deficient mouse and zebra fish models have been established to show consistent phenotypes with WAS patients, including thrombocytopenia, lymphopenia, defective T cell activation and defects in both the wound-induced inflammatory response and in immune-cell-mediated resistance to bacterial infection. Zebrafish WASp mutant can be rescued by WT hWASp. All of these types of evidence are consistent with a definitive relationship between the WAS gene and Wiskott-Aldrich syndrome.

X-linked severe congenital neutropeniaMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010294

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Wiskott-Aldrich syndrome; Thrombocytopenia 1; Neutropenia, severe congenital, X-linkedXL

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic

Intervention: Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic

Rationale: Prophylaxis and early and aggressive treatments for infections, and avoidance of circumstances that would result in severe bleeding, including certain medications, may be beneficial; HSCT, and genetically modified HSCT (gene therapy) have been described

Comments: Individuals can have immune dysfunction, such as in SCNX, which is due to constitutively activating variants

Refs: 13133561; 4177931; 4177932; 3995178; 3284030; 1960605; 8279047; 8069912; 7795648; 7537115; 1611094; 7579347; 8682510; 10575547; 8931701; 10447259; 11242115; 11447283; 15142877; 11238097; 11242115; 16804117; 17065640; 17065636; 17250667; 19006568; 18724301; 18479478; 20301357; 21067383; 22052860; 22338148; 22426750; 22456069; 22523910; 23023736; 23237501; 23264593; 23343520; 23498591; 23527602; 23845947; 23943155; 37478401; 38579284

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WAS variants in ClinVar

14 Conditions Cataloged

Wiskott-Aldrich syndromeTotal: 664

Thrombocytopenia 1Total: 611

X-linked severe congenital neutropeniaTotal: 608

not providedTotal: 145

not specifiedTotal: 81

WAS-related disorderTotal: 54

Inborn genetic diseasesTotal: 39

ThrombocytopeniaTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000377.3. 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	1 clinvar		5 clinvar	154 clinvar	10 clinvar	170
missense	22 clinvar	34 clinvar	202 clinvar	39 clinvar	8 clinvar	305
nonsense	28 clinvar	6 clinvar	1 clinvar			35
start loss	2 clinvar					2
frameshift	62 clinvar	24 clinvar	2 clinvar			88
splice donor/acceptor (+/-2bp)	27 clinvar	8 clinvar	6 clinvar			41
Total	142	72	216	193	18	641

Highest pathogenic variant AF is 0.000029347384

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000377.3	RefSeq	NP_000368.1	12	MANE Select
ENST00000376701.5	Ensembl	ENSP00000365891.4	12	MANE Select
NM_001438876.1	RefSeq	NP_001425805.1	12	Standard
NM_001438877.1	RefSeq	NP_001425806.1	12	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)
Endocytosis - Homo sapiens (human)

Biological Process

actin cortical patch assembly
regulation of T cell antigen processing and presentation
endocytosis
defense response
immune response

Molecular Function

protein binding
SH3 domain binding
protein kinase binding
GTPase regulator activity
small GTPase binding

Cellular Component

nucleus
cytosol
actin filament
cell-cell junction
vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376701
Coding exons: 12
Length: 14834
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	1.98	129	209	0.616	0.0000174	3153
Missense (PolyPhen)		22	71.019	0.30978		1016
Synonymous	0.617	80	87.3	0.916	0.00000771	1103
Loss of Function	4.15	0	20.0	0.00	0.00000176	263

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: Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex (PubMed:12235133, PubMed:12769847, PubMed:16275905). Important for efficient actin polymerization (PubMed:8625410, PubMed:12235133, PubMed:16275905). Possible regulator of lymphocyte and platelet function (PubMed:9405671). Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria (PubMed:18650809). In addition to its role in the cytoplasmic cytoskeleton, also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:20574068). Promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947). {ECO:0000269|PubMed:12235133, ECO:0000269|PubMed:12769847, ECO:0000269|PubMed:16275905, ECO:0000269|PubMed:18650809, ECO:0000269|PubMed:20574068, ECO:0000269|PubMed:29925947, ECO:0000269|PubMed:8625410, ECO:0000269|PubMed:9405671}.;
Disease: DISEASE: Wiskott-Aldrich syndrome (WAS) [MIM:301000]: An X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10. {ECO:0000269|PubMed:10447259, ECO:0000269|PubMed:11793485, ECO:0000269|PubMed:20574068, ECO:0000269|PubMed:7753869, ECO:0000269|PubMed:8528198, ECO:0000269|PubMed:8528199, ECO:0000269|PubMed:8682510, ECO:0000269|PubMed:9098856, ECO:0000269|PubMed:9126958, ECO:0000269|PubMed:9445409, ECO:0000269|PubMed:9683546, ECO:0000269|PubMed:9713366}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thrombocytopenia 1 (THC1) [MIM:313900]: Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. {ECO:0000269|PubMed:10447259, ECO:0000269|PubMed:11167787, ECO:0000269|PubMed:11877312, ECO:0000269|PubMed:7795648, ECO:0000269|PubMed:8528199}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neutropenia, severe congenital, X-linked (XLN) [MIM:300299]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. {ECO:0000269|PubMed:11242115}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.559

Intolerance Scores

RVIS EVS: 0.51
RVIS percentile EVS: 80.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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