WIPF1

protein-coding

WAS/WASL interacting protein family member 1

Gene summary

This gene encodes a protein that plays an important role in the organization of the actin cytoskeleton. The encoded protein binds to a region of Wiskott-Aldrich syndrome protein that is frequently mutated in Wiskott-Aldrich syndrome, an X-linked recessive disorder. Impairment of the interaction between these two proteins may contribute to the disease. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

WASPIP

MANE transcript

NM_001375834.1

Inheritance

ClinVar variants

P:6U:188B:142

Top phenotype

Wiskott-Aldrich syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr2:174,559,572-174,682,916

External References & Databases

Ensembl (ENSG00000115935)

Transcript & Mutation Effects

hg38 • Region Span ~123.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wiskott-Aldrich syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013779

Submitter: Ambry Genetics

Wiskott-Aldrich syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013779

Submitter: Labcorp Genetics (formerly Invitae)

Wiskott-Aldrich syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013779

Submitter: PanelApp Australia

Wiskott-Aldrich syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013779

Submitter: ClinGen

WIPF1 was first reported in relation to autosomal recessive WIPF1-related combined immunodeficiency with thrombocytopenia in 2012 (Lanzi et al., PMID: 22231303). Three nonsense variants that have been reported in 3 probands in 3 publications are included in this curation (PMIDs: 22231303, 27742395, 28903942). One variant segregated with disease in affected family members. Individuals affected with the condition present in infancy with recurrent infections, bloody diarrhea, thrombocytopenia with normal platelet volume, and inflammatory diseases such as eczema and pneumonitis. They have T cell lymphopenia affecting CD8+ lymphocytes most severely. T cell proliferation and chemotaxis are defective, and natural killer cell function is impaired. The clinical impact to heterozygous carriers is unknown. This gene-disease association is supported by protein interaction, functional and rescue assays, as well as an animal model (PMIDs: 9405671, 17141616, 22231303, 28903942, 11869681, 17086554). The mechanism of pathogenicity appears to be loss of function. One normal function of WIP is to bind to WASP, stabilizing the protein and preventing its degradation (PMID: 9405671, 17141616, 22231303). In the absence of WIP, WASP expression is reduced or absent despite normal levels of mRNA (PMID: 17141616, 22231303). Introduction of wild type WIPF1 corrects this defect (PMID: 22231303). WAS has been previously established as definitively associated with Wiskott-Aldrich syndrome, a combined immunodeficiency with thrombocytopenia. WIPF1 knockout mice recapitulate the patient phenotype with severe lymphopenia, splenomegaly, and inflammatory diseases including ulcerative colitis and interstitial pneumonitis (PMID: 11869681, 17086554). In summary, WIPF1 is definitively associated with autosomal recessive WIPF1-related combined immunodeficiency with thrombocytopenia. 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 March 16, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Wiskott-Aldrich syndrome 2AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: Individuals have been described with frequent and severe infections (including a lethal infectious course in one individual), and thus, antiinfectious prophylaxis and early and aggressive treatment of infections and bleeding issues may be beneficial; Unrelated CBT has been reported as effective

Refs: 22231303

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WIPF1 variants in ClinVar

5 Conditions Cataloged

Wiskott-Aldrich syndrome 2Total: 305

Inborn genetic diseasesTotal: 72

not specifiedTotal: 49

not providedTotal: 48

WIPF1-related disorderTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001375834.1. 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			3 clinvar	127 clinvar	3 clinvar	133
missense			180 clinvar	12 clinvar		192
nonsense	4 clinvar		1 clinvar			5
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	6	0	188	139	3	336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001375834.1	RefSeq	NP_001362763.1	7	MANE Select
ENST00000679041.1	Ensembl	ENSP00000503603.1	7	MANE Select
NM_001077269.1	RefSeq	NP_001070737.1	7	Standard
NM_001375832.1	RefSeq	NP_001362761.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Signal Transduction
Fcgamma receptor (FCGR) dependent phagocytosis
TCR
Innate Immune System

Biological Process

actin cortical patch assembly
endocytosis
actin polymerization or depolymerization
actin filament-based movement
Fc-gamma receptor signaling pathway involved in phagocytosis

Molecular Function

actin binding
protein binding
profilin binding
SH3 domain binding
actin filament binding

Cellular Component

ruffle
cytosol
actin filament
actin cytoskeleton
actin cortical patch

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392547
Coding exons: 7
Length: 123345
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	259	317	0.818	0.0000189	3155
Missense (PolyPhen)		117	164.78	0.71002		1584
Synonymous	0.560	127	135	0.939	0.00000935	1185
Loss of Function	3.29	2	16.3	0.122	9.46e-7	189

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the reorganization of the actin cytoskeleton. Contributes with NCK1 and GRB2 in the recruitment and activation of WASL. May participate in regulating the subcellular localization of WASL, resulting in the disassembly of stress fibers in favor of filopodia formation. Plays a role in the formation of cell ruffles (By similarity). Plays an important role in the intracellular motility of vaccinia virus by functioning as an adapter for recruiting WASL to vaccinia virus. {ECO:0000250, ECO:0000269|PubMed:10878810, ECO:0000269|PubMed:19910490, ECO:0000269|PubMed:9405671}.;
Disease: DISEASE: Wiskott-Aldrich syndrome 2 (WAS2) [MIM:614493]: An immunodeficiency disorder characterized by eczema, thrombocytopenia, recurrent infections, defective T-cell proliferation, and impaired natural killer cell function. {ECO:0000269|PubMed:22231303}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.152

Intolerance Scores

LoFtool: 0.145
RVIS EVS: -0.6
RVIS percentile EVS: 18.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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