WNT7A

protein-coding

Wnt family member 7A, the group of Wnt family

Gene summary

This gene is a member of the WNT gene family, which consists of structurally related genes that 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 involved in the development of the anterior-posterior axis in the female reproductive tract, and also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function. Mutations in this gene are associated with Fuhrmann and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndromes. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004625.4

Inheritance

ClinVar variants

P:10U:64B:32

Top phenotype

Ulna and fibula, absence of, with severe limb deficiency (Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome); Fibular aplasia or hypoplasia, femoral bowing, and poly-, syn-, and oligodactyly (Fuhrmann syndrome); Santos syndrome

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr3:13,816,258-13,880,071

External References & Databases

Ensembl (ENSG00000154764)

Transcript & Mutation Effects

hg38 • Region Span ~63.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

phocomelia, Schinzel typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010164

Submitter: Orphanet

phocomelia, Schinzel typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010164

Submitter: PanelApp Australia

Fuhrmann syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009232

Submitter: Labcorp Genetics (formerly Invitae)

Fuhrmann syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009232

Submitter: Orphanet

Fuhrmann syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009232

Submitter: G2P

Fuhrmann syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009232

Submitter: PanelApp Australia

Santos syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013077

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Manifestation: Dermatologic; Genitourinary; Musculoskeletal

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: 7363910; 3981578; 3400735; 3066902; 2338339; 1785629; 9128926; 11332978; 12868468; 16826533; 19012338; 19309796; 20949531; 21271649; 21344627; 28855715

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WNT7A variants in ClinVar

10 Conditions Cataloged

not providedTotal: 53

Inborn genetic diseasesTotal: 48

Schinzel phocomelia syndromeTotal: 12

WNT7A-related disorderTotal: 12

not specifiedTotal: 11

Fuhrmann syndromeTotal: 9

Santos syndromeTotal: 5

WNT7A-related disoderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004625.4. 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				26 clinvar	3 clinvar	29
missense	4 clinvar	2 clinvar	61 clinvar	3 clinvar		70
nonsense	1 clinvar	1 clinvar				2
start loss			1 clinvar			1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	1 clinvar			3
Total	6	4	64	29	3	106

Highest pathogenic variant AF is 0.0000041094763

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004625.4	RefSeq	NP_004616.2	4	MANE Select
ENST00000285018.5	Ensembl	ENSP00000285018.4	4	MANE Select
ENST00001138497.1	Ensembl	ENSP00000804575.1	4	Standard
XM_011534091.3	RefSeq	XP_011532393.1	3	Standard

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

embryonic axis specification
cartilage condensation
angiogenesis
chondrocyte differentiation
neurotransmitter secretion

Molecular Function

signaling receptor binding
frizzled binding
cytokine activity
protein binding
receptor ligand activity

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
Golgi lumen
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000285018
Coding exons: 4
Length: 63864
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.34	186	245	0.758	0.0000180	2282
Missense (PolyPhen)		39	90.45	0.43118		799
Synonymous	-0.773	115	105	1.10	0.00000863	678
Loss of Function	2.36	5	14.8	0.338	7.25e-7	161

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
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	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ligand for members of the frizzled family of seven transmembrane receptors. Functions in the canonical Wnt/beta- catenin signaling pathway (By similarity). Plays an important role in embryonic development, including dorsal versus ventral patterning during limb development, skeleton development and urogenital tract development (PubMed:16826533). Required for normal, sexually dimorphic development of the Mullerian ducts, and for normal fertility in both sexes. Required for normal neural stem cell proliferation in the hippocampus dentate gyrus. Required for normal progress through the cell cycle in neural progenitor cells, for self-renewal of neural stem cells, and for normal neuronal differentiation and maturation. Promotes formation of synapses via its interaction with FZD5 (By similarity). {ECO:0000250|UniProtKB:P24383, ECO:0000269|PubMed:16826533}.;
Disease: DISEASE: Limb pelvis hypoplasia aplasia syndrome (LPHAS) [MIM:276820]: A syndrome of severe deficiency of the extremities due to hypo- or aplasia of one or more long bones of one or more limbs. Pelvic manifestations include hip dislocation, hypoplastic iliac bone and aplastic pubic bones. Thoracic deformity, unusual facies and genitourinary anomalies can be present. {ECO:0000269|PubMed:16826533, ECO:0000269|PubMed:17431918, ECO:0000269|PubMed:20949531, ECO:0000269|PubMed:21271649, ECO:0000269|PubMed:27638328}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fuhrmann syndrome (FUHRS) [MIM:228930]: Distinct limb- malformation disorder characterized also by various degrees of limb aplasia/hypoplasia and joint dysplasia. {ECO:0000269|PubMed:16826533}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.288

Intolerance Scores

LoFtool: 0.288
RVIS EVS: -0.67
RVIS percentile EVS: 15.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.804

Gene Damage Prediction

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