RSPO1

R-spondin 1, the group of R-spondin family

Basic information

Region (hg38): 1:37611350-37634892

Links

ENSG00000169218 ∙ NCBI:284654 ∙ OMIM:609595 ∙ HGNC:21679 ∙ Uniprot:Q2MKA7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (Strong), mode of inheritance: AR
• palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (Moderate), mode of inheritance: AR
• palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (Strong), mode of inheritance: AR
• palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and 46,XX sex reversal	AR	Genitourinary; Oncologic	Surveillance/treatment of gonadal tumors and specific malignancies may improve outcome	Audiologic/Otolaryngologic; Dermatologic; Endocrine; Genitourinary; Oncologic; Ophthalmologic	17041600; 18085567

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RSPO1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RSPO1 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			1	10		11
missense			21	1	2	24
nonsense						0
start loss						0
frameshift			1			1
inframe indel					1	1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1	11	12
Total	0	0	23	12	14

Variants in RSPO1

This is a list of pathogenic ClinVar variants found in the RSPO1 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-37612499-G-GGT			Benign (Jun 19, 2021)
1-37612499-G-GGTGT			Benign (Jun 21, 2021)
1-37612628-A-G			Benign (Nov 12, 2018)
1-37612794-T-TTGC		not specified	Benign (Jan 18, 2024)
1-37612828-C-T			Benign (Jan 15, 2024)
1-37612875-G-T		Inborn genetic diseases	Uncertain significance (Oct 26, 2022)
1-37612886-C-T		Inborn genetic diseases	Uncertain significance (May 13, 2024)
1-37612888-C-T		Inborn genetic diseases	Uncertain significance (Dec 13, 2022)
1-37612889-G-A			Conflicting classifications of pathogenicity (Feb 17, 2023)
1-37612908-C-T			Likely benign (Aug 17, 2023)
1-37612958-A-T			Benign (Jun 20, 2021)
1-37613709-G-A		Inborn genetic diseases	Uncertain significance (Jan 17, 2024)
1-37613714-C-T			Likely benign (Dec 15, 2023)
1-37613721-C-T		Inborn genetic diseases	Uncertain significance (Dec 27, 2022)
1-37613743-TC-T			Uncertain significance (Jan 03, 2023)
1-37613744-C-A		Inborn genetic diseases	Uncertain significance (Mar 11, 2024)
1-37613776-C-A			Likely benign (Oct 11, 2023)
1-37613813-G-A			Likely benign (Apr 13, 2023)
1-37613822-C-T			Likely benign (Oct 05, 2022)
1-37613824-G-A			Uncertain significance (Jan 24, 2023)
1-37613845-T-G			Benign (Jan 26, 2024)
1-37613848-T-C			Uncertain significance (Jul 06, 2022)
1-37613865-G-A			Uncertain significance (Jul 18, 2022)
1-37613868-G-A			Uncertain significance (Aug 08, 2022)
1-37613875-C-T		Inborn genetic diseases	Uncertain significance (Jun 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RSPO1	protein_coding	protein_coding	ENST00000356545	5	23645

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000144	0.406	124795	0	22	124817	0.0000881

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.647	138	161	0.857	0.0000109	1706
Missense in Polyphen		36	49.682	0.72462		498
Synonymous	-0.473	70	65.1	1.07	0.00000426	514
Loss of Function	0.558	10	12.1	0.827	5.93e-7	146

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000158	0.000158
Ashkenazi Jewish	0.0000993	0.0000993
East Asian	0.0000556	0.0000556
Finnish	0.0000934	0.0000928
European (Non-Finnish)	0.000106	0.000106
Middle Eastern	0.0000556	0.0000556
South Asian	0.0000654	0.0000654
Other	0.000165	0.000165

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. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1-mediated internalization of LRP6 through an interaction with KREM1 (PubMed:17804805). {ECO:0000269|PubMed:16109882, ECO:0000269|PubMed:17804805, ECO:0000269|PubMed:21727895, ECO:0000269|PubMed:21909076, ECO:0000269|PubMed:22575959, ECO:0000269|PubMed:22615920, ECO:0000269|PubMed:22815884, ECO:0000269|PubMed:23756652, ECO:0000269|PubMed:23809763}.
• Disease: DISEASE: Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal (PKKSCC) [MIM:610644]: A recessive syndrome characterized by XX (female to male) SRY-independent sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. {ECO:0000269|PubMed:17041600}. 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;Wnt;Wnt signaling network;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.170

Intolerance Scores

• loftool: 0.423
• rvis_EVS: 0.17
• rvis_percentile_EVS: 65.76

Haploinsufficiency Scores

• pHI: 0.261
• hipred: N
• hipred_score: 0.342
• ghis: 0.426

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.126

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rspo1
• Phenotype: homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); 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); 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; skeleton phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: rspo1
• Affected structure: vascular sprouts
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: positive regulation of protein phosphorylation;regulation of receptor internalization;Wnt signaling pathway;positive regulation of Wnt signaling pathway;positive regulation of canonical Wnt signaling pathway
• Cellular component: extracellular region;extracellular space;nucleus
• Molecular function: G protein-coupled receptor binding;signaling receptor binding;frizzled binding;protein binding;heparin binding