RSPO4

R-spondin 4, the group of R-spondin family

Basic information

Region (hg38): 20:958451-1002311

Previous symbols: [ "C20orf182" ]

Links

ENSG00000101282 ∙ NCBI:343637 ∙ OMIM:610573 ∙ HGNC:16175 ∙ Uniprot:Q2I0M5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nonsyndromic congenital nail disorder 4 (Definitive), mode of inheritance: AR
• nonsyndromic congenital nail disorder 4 (Strong), mode of inheritance: AR
• nonsyndromic congenital nail disorder 4 (Supportive), mode of inheritance: AR
• nonsyndromic congenital nail disorder 4 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Anonychia/hyponychia congenita	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	Dermatologic	4702713; 17186469; 17041604; 17914448; 18070203; 22300369

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RSPO4 gene.

• Inborn genetic diseases (16 variants)
• not provided (4 variants)
• Anonychia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RSPO4 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						0
missense			15	1	1	17
nonsense						0
start loss						0
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)	1					1
splice region						0
non coding						0
Total	2	0	15	1	1

Highest pathogenic variant AF is 0.000131

Variants in RSPO4

This is a list of pathogenic ClinVar variants found in the RSPO4 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-960371-C-T		Inborn genetic diseases	Uncertain significance (Dec 14, 2023)
20-960381-C-T		RSPO4-related disorder	Likely benign (Apr 29, 2019)
20-960382-G-T		Inborn genetic diseases	Uncertain significance (Feb 21, 2024)
20-960389-C-G		Inborn genetic diseases	Uncertain significance (Sep 20, 2023)
20-960401-G-A		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
20-960428-G-A		Inborn genetic diseases	Uncertain significance (May 08, 2023)
20-960442-C-T		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
20-963952-T-C		Inborn genetic diseases	Likely benign (Jan 29, 2024)
20-963959-G-A		RSPO4-related disorder	Benign (Oct 28, 2019)
20-963960-A-C		Inborn genetic diseases	Uncertain significance (Feb 22, 2023)
20-964004-C-T		Inborn genetic diseases	Uncertain significance (Jun 28, 2022)
20-964054-G-A		Inborn genetic diseases	Uncertain significance (Mar 12, 2024)
20-964072-T-C		Inborn genetic diseases	Uncertain significance (Dec 13, 2023)
20-964075-T-G		Inborn genetic diseases • RSPO4-related disorder	Conflicting classifications of pathogenicity (Oct 18, 2021)
20-964094-C-T		Inborn genetic diseases	Likely benign (Mar 15, 2023)
20-964098-C-A		Inborn genetic diseases	Uncertain significance (Sep 14, 2022)
20-964106-C-T		Inborn genetic diseases	Uncertain significance (Aug 30, 2022)
20-967186-G-A		Inborn genetic diseases	Uncertain significance (Sep 06, 2022)
20-967223-G-A		RSPO4-related disorder	Likely benign (Sep 05, 2019)
20-967230-C-T		Anonychia	Pathogenic (Nov 01, 2006)
20-967245-A-G		Inborn genetic diseases	Uncertain significance (Aug 30, 2021)
20-967257-C-G		Inborn genetic diseases	Uncertain significance (Jun 21, 2023)
20-967263-C-T			Uncertain significance (Oct 28, 2022)
20-967264-A-G		Anonychia	Pathogenic (Nov 01, 2006)
20-967266-C-T			Benign (May 18, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RSPO4	protein_coding	protein_coding	ENST00000217260	5	43813

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.60e-8	0.170	124769	0	28	124797	0.000112

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.470	166	150	1.11	0.0000100	1491
Missense in Polyphen		68	55.143	1.2332		542
Synonymous	-1.02	70	59.9	1.17	0.00000373	458
Loss of Function	0.0796	11	11.3	0.974	5.86e-7	121

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000395	0.000381
Ashkenazi Jewish	0.00	0.00
East Asian	0.000223	0.000223
Finnish	0.00	0.00
European (Non-Finnish)	0.0000979	0.0000971
Middle Eastern	0.000223	0.000223
South Asian	0.000196	0.000196
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. {ECO:0000269|PubMed:21727895, ECO:0000269|PubMed:21909076}.
• Disease: DISEASE: Nail disorder, non-syndromic congenital, 4 (NDNC4) [MIM:206800]: A nail disorder characterized by congenital anonychia or its milder phenotypic variant hyponychia. Anonychia/hyponychia is the absence or severe hypoplasia of all fingernails and toenails without significant bone anomalies. {ECO:0000269|PubMed:17041604}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signaling by WNT;Signal Transduction;Regulation of FZD by ubiquitination;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.138

Intolerance Scores

• loftool: 0.297
• rvis_EVS: 0.31
• rvis_percentile_EVS: 72.38

Haploinsufficiency Scores

• pHI: 0.199
• hipred: N
• hipred_score: 0.238
• ghis: 0.419

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 2.22e-16

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rspo4

Gene ontology

• Biological process: Wnt signaling pathway;positive regulation of Wnt signaling pathway;nail development;positive regulation of canonical Wnt signaling pathway
• Cellular component: extracellular region;extracellular space
• Molecular function: frizzled binding;heparin binding