WNT1

Wnt family member 1, the group of Wnt family

Basic information

Region (hg38): 12:48978322-48982620

Previous symbols: [ "INT1" ]

Links

ENSG00000125084 ∙ NCBI:7471 ∙ OMIM:164820 ∙ HGNC:12774 ∙ Uniprot:P04628 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• osteogenesis imperfecta type 3 (Supportive), mode of inheritance: AD
• osteogenesis imperfecta type 4 (Supportive), mode of inheritance: AD
• osteogenesis imperfecta type 15 (Strong), mode of inheritance: AR
• idiopathic juvenile osteoporosis (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Osteoprosis, autosomal dominant; Osteogenesis imperfecta, type XV	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	Musculoskeletal	23434763; 23499309; 23499310; 23656646
The use of bisphosphonates has been described to treat osteogenesis imperfecta, but it is unclear if an early (genetic) diagnosis would be advantageous

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WNT1 gene.

• not provided (16 variants)
• Osteogenesis imperfecta type 15 (4 variants)
• Osteogenesis imperfecta (1 variants)
• Inborn genetic diseases (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WNT1 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			3	39	1	43
missense		4	107	2		113
nonsense	7					7
start loss	1					1
frameshift	9	5	5			19
inframe indel						0
splice donor/acceptor (+/-2bp)	1					1
splice region		1	4	1		6
non coding				11		11
Total	18	9	115	52	1

Highest pathogenic variant AF is 0.0000131

Variants in WNT1

This is a list of pathogenic ClinVar variants found in the WNT1 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-48978652-TG-T		WNT1-related disorder	Likely pathogenic (Aug 05, 2023)
12-48978653-G-A			Pathogenic (Mar 26, 2022)
12-48978655-GG-AA			Uncertain significance (Dec 13, 2021)
12-48978658-T-A		Inborn genetic diseases	Likely benign (Apr 07, 2023)
12-48978665-G-T			Likely benign (Dec 04, 2022)
12-48978673-C-T		Osteogenesis imperfecta	Uncertain significance (Aug 01, 2019)
12-48978677-C-T		Osteogenesis imperfecta	Uncertain significance (Sep 02, 2021)
12-48978702-G-A		Inborn genetic diseases • not specified	Uncertain significance (Jun 20, 2024)
12-48978702-G-T			Uncertain significance (Jul 16, 2021)
12-48978730-C-T			Uncertain significance (Aug 16, 2023)
12-48978743-T-C			Likely benign (Mar 23, 2023)
12-48978748-G-T			Uncertain significance (Dec 16, 2023)
12-48978752-G-A			Pathogenic (Oct 09, 2023)
12-48978755-G-A			Pathogenic (Jul 19, 2022)
12-48978756-TAAGTGAGCTGGTGCGGGGTCGCCACTTGTCCCGCGGCACAG-T		Osteogenesis imperfecta type 15	Likely pathogenic (Nov 29, 2017)
12-48978760-T-C			Uncertain significance (Jul 12, 2022)
12-48979249-C-G			Likely benign (Nov 08, 2018)
12-48979462-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jul 24, 2023)
12-48979474-T-C			Likely benign (Nov 08, 2022)
12-48979475-G-A			Uncertain significance (Oct 07, 2022)
12-48979481-G-A		Inborn genetic diseases	Uncertain significance (Dec 01, 2022)
12-48979482-T-C			Uncertain significance (Apr 09, 2023)
12-48979495-G-A			Uncertain significance (Jan 29, 2024)
12-48979515-A-G			Uncertain significance (Feb 08, 2024)
12-48979517-A-G			Uncertain significance (Feb 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WNT1	protein_coding	protein_coding	ENST00000293549	4	3062

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.326	0.671	125699	0	12	125711	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.06	166	209	0.794	0.00000961	2336
Missense in Polyphen		64	88.176	0.72582		977
Synonymous	2.27	64	91.6	0.699	0.00000433	788
Loss of Function	2.55	3	12.9	0.233	5.64e-7	130

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000337	0.000326
Finnish	0.0000739	0.0000462
European (Non-Finnish)	0.0000194	0.0000176
Middle Eastern	0.000337	0.000326
South Asian	0.0000329	0.0000327
Other	0.000183	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Acts in the canonical Wnt signaling pathway by promoting beta-catenin-dependent transcriptional activation (PubMed:23499309, PubMed:26902720, PubMed:28528193, PubMed:23656646). In some developmental processes, is also a ligand for the coreceptor RYK, thus triggering Wnt signaling (By similarity). Plays an essential role in the development of the embryonic brain and central nervous system (CNS) (By similarity). Has a role in osteoblast function, bone development and bone homeostasis (PubMed:23499309, PubMed:23656646). {ECO:0000250|UniProtKB:P04426, ECO:0000269|PubMed:23499309, ECO:0000269|PubMed:23656646, ECO:0000269|PubMed:26902720, ECO:0000269|PubMed:28528193, ECO:0000305}.
• Disease: DISEASE: Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. {ECO:0000269|PubMed:23499309, ECO:0000269|PubMed:23656646}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Osteogenesis imperfecta 15 (OI15) [MIM:615220]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI15 is characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclerae. Tooth development and hearing are normal. Learning and developmental delays and brain anomalies have been observed in some patients. {ECO:0000269|PubMed:23434763, ECO:0000269|PubMed:23499309, ECO:0000269|PubMed:23499310, ECO:0000269|PubMed:23656646}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteogenesis imperfecta 14 (OI14) [MIM:615066]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI14 is characterized by variable degrees of severity of multiple fractures and osteopenia, with normal teeth, sclerae, and hearing. Fractures first occur prenatally or by age 6 years. {ECO:0000269|PubMed:28528193}. 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);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Basal cell carcinoma - Homo sapiens (human);Hepatocellular carcinoma - 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;Neural Crest Differentiation;Adipogenesis;Primary Focal Segmental Glomerulosclerosis FSGS;Differentiation Pathway;Dopaminergic Neurogenesis;Ectoderm Differentiation;Hypothetical Craniofacial Development Pathway;Wnt-beta-catenin Signaling Pathway in Leukemia;Regulation of Wnt-B-catenin Signaling by Small Molecule Compounds;ESC Pluripotency Pathways;Wnt Signaling Pathway and Pluripotency;Wnt Signaling in Kidney Disease;EMT transition in Colorectal Cancer;Wnt Signaling Pathway;TGF-beta Receptor Signaling;DNA Damage Response (only ATM dependent);Signaling by GPCR;Signaling by WNT;Signal Transduction;wnt signaling pathway;segmentation clock;multi-step regulation of transcription by pitx2;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;Disassembly of the destruction complex and recruitment of AXIN to the membrane;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;Beta-catenin independent WNT signaling;C-MYB transcription factor network;WNT ligand biogenesis and trafficking;GPCR signaling-G alpha i;Wnt;Wnt Canonical;Wnt signaling network;TCF dependent signaling in response to WNT;Wnt Mammals;Presenilin action in Notch and Wnt signaling (Consensus)

Recessive Scores

• pRec: 0.785

Intolerance Scores

• loftool: 0.337
• rvis_EVS: 0.1
• rvis_percentile_EVS: 61.28

Haploinsufficiency Scores

• pHI: 0.417
• hipred: Y
• hipred_score: 0.856
• ghis: 0.469

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.993

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wnt1
• Phenotype: hematopoietic system 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; skeleton phenotype; immune system phenotype; muscle phenotype; hearing/vestibular/ear 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); endocrine/exocrine gland phenotype; cellular phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: wnt1
• Affected structure: glial cell
• Phenotype tag: abnormal
• Phenotype quality: mislocalised

Gene ontology

• Biological process: embryonic axis specification;branching involved in ureteric bud morphogenesis;positive regulation of protein phosphorylation;cell-cell signaling;myoblast fusion;positive regulation of cell population proliferation;response to wounding;regulation of signaling receptor activity;positive regulation of lamellipodium assembly;negative regulation of cell-substrate adhesion;Wnt signaling pathway;spinal cord association neuron differentiation;diencephalon development;central nervous system morphogenesis;cerebellum formation;forebrain anterior/posterior pattern specification;midbrain-hindbrain boundary maturation during brain development;negative regulation of cell-cell adhesion;neuron differentiation;negative regulation of transforming growth factor beta receptor signaling pathway;negative regulation of BMP signaling pathway;ubiquitin-dependent SMAD protein catabolic process;midbrain development;animal organ regeneration;T cell differentiation in thymus;cell proliferation in midbrain;astrocyte-dopaminergic neuron signaling;inner ear morphogenesis;signal transduction in response to DNA damage;negative regulation of apoptotic process;positive regulation of insulin-like growth factor receptor signaling pathway;cell fate commitment;negative regulation of fat cell differentiation;positive regulation of Notch signaling pathway;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of fibroblast proliferation;neuron fate determination;positive regulation of DNA-binding transcription factor activity;Spemann organizer formation;canonical Wnt signaling pathway;Wnt signaling pathway, planar cell polarity pathway;bone development;positive regulation of dermatome development;hepatocyte differentiation;cellular response to peptide hormone stimulus;hematopoietic stem cell proliferation;negative regulation of cell aging;negative regulation of oxidative stress-induced neuron death;beta-catenin destruction complex disassembly;Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation;canonical Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation;embryonic brain development;negative regulation of ubiquitin-dependent protein catabolic process
• Cellular component: extracellular region;extracellular space;cytoplasm;endoplasmic reticulum lumen;Golgi lumen;plasma membrane;cell surface;endocytic vesicle membrane;extracellular exosome
• Molecular function: frizzled binding;cytokine activity;morphogen activity;protein domain specific binding;transcription regulatory region DNA binding;receptor ligand activity