WNT4

protein-coding

Wnt family member 4, the group of Wnt family

Gene summary

The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, and is the first signaling molecule shown to influence the sex-determination cascade. It encodes a protein which shows 98% amino acid identity to the Wnt4 protein of mouse and rat. This gene and a nuclear receptor known to antagonize the testis-determining factor play a concerted role in both the control of female development and the prevention of testes formation. This gene and another two family members, WNT2 and WNT7B, may be associated with abnormal proliferation in breast tissue. Mutations in this gene can result in Rokitansky-Kuster-Hauser syndrome and in SERKAL syndrome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_030761.5

Inheritance

AD, AR

ClinVar variants

P:5U:93B:44

Top phenotype

Mullerian aplasia and hyperandrogenism; 46,XX sex reversal with dysgenesis of kidneys, adrenals, and lungs (SERKAL syndrome)

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr1:22,117,313-22,143,969

External References & Databases

Ensembl (ENSG00000162552)

Transcript & Mutation Effects

hg38 • Region Span ~26.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SERKAL syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012734

Submitter: Labcorp Genetics (formerly Invitae)

mullerian aplasia and hyperandrogenismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008019

Submitter: G2P

mullerian aplasia and hyperandrogenismMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008019

Submitter: Ambry Genetics

SERKAL syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012734

Submitter: G2P

mullerian aplasia and hyperandrogenismMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008019

Submitter: PanelApp Australia

SERKAL syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012734

Submitter: Orphanet

SERKAL syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012734

Submitter: PanelApp Australia

SERKAL syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012734

Submitter: Ambry Genetics

mullerian aplasia and hyperandrogenismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008019

Submitter: Labcorp Genetics (formerly Invitae)

mullerian aplasia and hyperandrogenismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008019

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mullerian aplasia and hyperandrogenism; 46,XX sex reversal with dysgenesis of kidneys, adrenals, and lungs (SERKAL syndrome)AD/AR

Manifestation: Cardiovascular; Endocrine; Genitourinary; Musculoskeletal; Pulmonary; Renal

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: 15317892; 16959810; 18179883; 18182450

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WNT4 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 98

Mullerian aplasia and hyperandrogenismTotal: 49

SERKAL syndromeTotal: 47

Inborn genetic diseasesTotal: 30

WNT4-related disorderTotal: 11

not specifiedTotal: 4

Mayer-Rokitansky-Kuster-Hauser syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030761.5. 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			4 clinvar	36 clinvar	3 clinvar	43
missense	5 clinvar		89 clinvar	4 clinvar	1 clinvar	99
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	5	0	93	40	4	142

Highest pathogenic variant AF is 0.000006816303

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030761.5	RefSeq	NP_110388.2	5	MANE Select
ENST00000290167.11	Ensembl	ENSP00000290167.5	5	MANE Select
ENST00000415567.1	Ensembl	ENSP00000403334.1	2	Standard
ENST00000441048.1	Ensembl	ENSP00000388925.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wnt4a	Danio rerio	Structure: ceratobranchial cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

wnt4a

Danio rerio

Structure: ceratobranchial cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

branching involved in ureteric bud morphogenesis
kidney development
epithelial to mesenchymal transition
embryonic epithelial tube formation
liver development

Molecular Function

transcription corepressor activity
frizzled binding
receptor ligand activity

Cellular Component

extracellular region
extracellular space
cytoplasm
endoplasmic reticulum lumen
Golgi lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290167
Coding exons: 5
Length: 26665
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125743
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.61	152	219	0.694	0.0000170	2254
Missense (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

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)	0.000053	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.440

Intolerance Scores

LoFtool: 0.400
RVIS EVS: -0.82
RVIS percentile EVS: 11.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.981

Gene Damage Prediction

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