WNT4

Wnt family member 4, the group of Wnt family

Basic information

Region (hg38): 1:22117312-22143969

Links

ENSG00000162552 ∙ NCBI:54361 ∙ OMIM:603490 ∙ HGNC:12783 ∙ Uniprot:P56705 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• SERKAL syndrome (Strong), mode of inheritance: AR
• mullerian aplasia and hyperandrogenism (Strong), mode of inheritance: AD
• SERKAL syndrome (Limited), mode of inheritance: AR
• mullerian aplasia and hyperandrogenism (Moderate), mode of inheritance: AD
• SERKAL syndrome (Supportive), mode of inheritance: AR
• mullerian aplasia and hyperandrogenism (Supportive), mode of inheritance: AD
• mullerian aplasia and hyperandrogenism (Strong), mode of inheritance: AD
• SERKAL syndrome (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mullerian aplasia and hyperandrogenism; 46,XX sex reversal with dysgenesis of kidneys, adrenals, and lungs (SERKAL syndrome)	AD/AR	General	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	Cardiovascular; Endocrine; Genitourinary; Musculoskeletal; Pulmonary; Renal	15317892; 16959810; 18179883; 18182450

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WNT4 gene.

• not provided (49 variants)
• Inborn genetic diseases (9 variants)
• SERKAL syndrome;Mullerian aplasia and hyperandrogenism (4 variants)
• Mullerian aplasia and hyperandrogenism (3 variants)
• WNT4-related condition (2 variants)
• not specified (1 variants)
• Mullerian aplasia and hyperandrogenism;SERKAL syndrome (1 variants)
• SERKAL syndrome (1 variants)
• Mayer-Rokitansky-Kuster-Hauser syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WNT4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				16	4	20
missense			30	1	1	32
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				5	6	11
Total	0	0	30	22	11

Variants in WNT4

This is a list of pathogenic ClinVar variants found in the WNT4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-22120059-C-T			Likely benign (Jul 26, 2023)
1-22120073-C-T			Uncertain significance (Nov 27, 2023)
1-22120074-G-A		WNT4-related disorder	Likely benign (Jul 24, 2019)
1-22120078-C-T		Inborn genetic diseases	Uncertain significance (Feb 16, 2023)
1-22120090-C-T		Inborn genetic diseases	Uncertain significance (Dec 06, 2022)
1-22120095-C-T			Likely benign (Dec 20, 2023)
1-22120100-C-T		Inborn genetic diseases	Uncertain significance (Jan 24, 2023)
1-22120101-G-A			Likely benign (Nov 04, 2022)
1-22120149-C-G			Uncertain significance (Dec 08, 2022)
1-22120152-C-T			Likely benign (Jan 25, 2024)
1-22120153-G-A		Inborn genetic diseases	Uncertain significance (Dec 09, 2023)
1-22120155-C-T			Likely benign (Dec 07, 2022)
1-22120162-A-C		SERKAL syndrome • Mullerian aplasia and hyperandrogenism • Mayer-Rokitansky-Kuster-Hauser syndrome	Uncertain significance (Aug 07, 2018)
1-22120166-C-T			Uncertain significance (Jan 06, 2023)
1-22120167-G-A			Likely benign (Nov 28, 2022)
1-22120168-C-T			Uncertain significance (Mar 11, 2022)
1-22120194-G-A			Likely benign (Sep 28, 2022)
1-22120196-C-T			Uncertain significance (Oct 17, 2022)
1-22120197-G-A		Mullerian aplasia and hyperandrogenism;SERKAL syndrome	Benign/Likely benign (Nov 15, 2023)
1-22120209-C-A		Mullerian aplasia and hyperandrogenism;SERKAL syndrome	Likely benign (Oct 04, 2023)
1-22120216-T-G			Uncertain significance (Mar 29, 2022)
1-22120225-C-T		Mullerian aplasia and hyperandrogenism	Uncertain significance (Dec 19, 2021)
1-22120231-C-G			Uncertain significance (Jun 03, 2023)
1-22120245-G-A			Likely benign (Jan 03, 2024)
1-22120247-C-T		Inborn genetic diseases	Uncertain significance (Jun 05, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WNT4	protein_coding	protein_coding	ENST00000290167	5	26665

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.128	0.868	125736	0	7	125743	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.61	152	219	0.694	0.0000170	2254
Missense in Polyphen		48	91.222	0.52619		888
Synonymous	-0.392	103	98.1	1.05	0.00000817	716
Loss of Function	2.49	4	14.1	0.284	7.04e-7	165

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000529	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Ligand for members of the frizzled family of seven transmembrane receptors. Probable developmental protein. May be a signaling molecule which affects the development of discrete regions of tissues. Is likely to signal over only few cell diameters (By similarity). Overexpression may be associated with abnormal proliferation in human breast tissue. {ECO:0000250}.
• Disease: DISEASE: 46,XX sex reversal with dysgenesis of kidneys, adrenals, and lungs (SERKAL) [MIM:611812]: A disease characterized by the association of female-to-male sex reversal with dysgenesis of kidneys, adrenals, and lungs. {ECO:0000269|PubMed:18179883}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mullerian aplasia and hyperandrogenism (MULLAPL) [MIM:158330]: A disorder of sex development. Affected females manifest dysgenesis of Mullerian duct derivatives absent or rudimentary uterus and vagina, functional ovaries, primary amenorrhea, hyperandrogenism and hirsutism. {ECO:0000269|PubMed:15317892, ECO:0000269|PubMed:16959810, ECO:0000269|PubMed:18182450}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Gastric cancer - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Breast cancer - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Axon guidance - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Basal cell carcinoma - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);WNT-Core;BMP2-WNT4-FOXO1 Pathway in Human Primary Endometrial Stromal Cell Differentiation;ESC Pluripotency Pathways;Wnt Signaling Pathway and Pluripotency;Wnt Signaling in Kidney Disease;EMT transition in Colorectal Cancer;Wnt Signaling Pathway;DNA Damage Response (only ATM dependent);Signaling by GPCR;Signaling by WNT;Signal Transduction;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;PCP/CE pathway;Negative regulation of TCF-dependent signaling by WNT ligand antagonists;Beta-catenin independent WNT signaling;WNT ligand biogenesis and trafficking;GPCR signaling-G alpha i;Wnt;Wnt Canonical;TCF dependent signaling in response to WNT;Wnt Mammals (Consensus)

Recessive Scores

• pRec: 0.440

Intolerance Scores

• loftool: 0.400
• rvis_EVS: -0.82
• rvis_percentile_EVS: 11.68

Haploinsufficiency Scores

• pHI: 0.957
• hipred: Y
• hipred_score: 0.719
• ghis: 0.606

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.981

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wnt4
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); cellular phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hematopoietic system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; embryo phenotype; renal/urinary system phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: wnt4a
• Affected structure: ceratobranchial cartilage
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: branching involved in ureteric bud morphogenesis;kidney development;epithelial to mesenchymal transition;embryonic epithelial tube formation;liver development;male gonad development;female gonad development;cellular response to starvation;regulation of signaling receptor activity;negative regulation of gene expression;negative regulation of steroid biosynthetic process;Wnt signaling pathway;regulation of cell-cell adhesion;neuron differentiation;female sex determination;adrenal gland development;negative regulation of cell migration;positive regulation of bone mineralization;positive regulation of aldosterone biosynthetic process;positive regulation of collagen biosynthetic process;immature T cell proliferation in thymus;non-canonical Wnt signaling pathway via MAPK cascade;negative regulation of fibroblast growth factor receptor signaling pathway;hormone metabolic process;positive regulation of GTPase activity;cell fate commitment;negative regulation of cell differentiation;positive regulation of osteoblast differentiation;positive regulation of meiotic nuclear division;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;oocyte development;smooth muscle cell differentiation;positive regulation of stress fiber assembly;positive regulation of focal adhesion assembly;canonical Wnt signaling pathway;somatotropin secreting cell differentiation;thyroid-stimulating hormone-secreting cell differentiation;mesenchymal to epithelial transition;tertiary branching involved in mammary gland duct morphogenesis;negative regulation of wound healing;mammary gland epithelium development;positive regulation of dermatome development;paramesonephric duct development;negative regulation of testicular blood vessel morphogenesis;cellular response to transforming growth factor beta stimulus;renal vesicle formation;renal vesicle induction;metanephric mesenchymal cell differentiation;metanephric tubule formation;metanephric nephron morphogenesis;negative regulation of male gonad development;positive regulation of cortisol biosynthetic process;negative regulation of androgen biosynthetic process;negative regulation of testosterone biosynthetic process;negative regulation of apoptotic signaling pathway
• Cellular component: extracellular region;extracellular space;cytoplasm;endoplasmic reticulum lumen;Golgi lumen;plasma membrane;cell surface;endocytic vesicle membrane;extracellular matrix;extracellular exosome
• Molecular function: transcription corepressor activity;frizzled binding;receptor ligand activity