SPRED1

sprouty related EVH1 domain containing 1, the group of Protein phosphatase 1 regulatory subunits

Basic information

Region (hg38): 15:38252835-38357249

Links

ENSG00000166068 ∙ NCBI:161742 ∙ OMIM:609291 ∙ HGNC:20249 ∙ Uniprot:Q7Z699 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Legius syndrome (Strong), mode of inheritance: AD
• Legius syndrome (Definitive), mode of inheritance: AD
• Legius syndrome (Strong), mode of inheritance: AD
• Legius syndrome (Supportive), mode of inheritance: AD
• Legius syndrome (Definitive), mode of inheritance: AD
• Legius syndrome (Strong), mode of inheritance: AD
• Legius syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Legius syndrome	AD	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	Craniofacial; Dermatologic; Musculoskeletal; Neurologic	17704776; 19366998; 19443465; 19920235; 20179001; 21649642; 21548021; 20945555; 22753041; 23401230
Oncologic processes are reported in some individuals, but the overall risk is unclear, and it has been stated that the condition does not involve tumor predisposition

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPRED1 gene.

• Legius syndrome (585 variants)
• not provided (121 variants)
• Cardiovascular phenotype (110 variants)
• not specified (69 variants)
• Noonan syndrome and Noonan-related syndrome (43 variants)
• Inborn genetic diseases (14 variants)
• Noonan syndrome (5 variants)
• SPRED1-related condition (2 variants)
• Neurofibromatosis-Noonan syndrome (1 variants)
• Neurodevelopmental delay (1 variants)
• Neurofibromatosis (1 variants)
• RASopathy (1 variants)
• Costello syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPRED1 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			2	100	2	104
missense		3	247	9	4	263
nonsense	26	6	1			33
start loss	2	1				3
frameshift	40	19	2			61
inframe indel			3			3
splice donor/acceptor (+/-2bp)	2	8				10
splice region			9	8	1	18
non coding			79	61	39	179
Total	70	37	334	170	45

Highest pathogenic variant AF is 0.0000132

Variants in SPRED1

This is a list of pathogenic ClinVar variants found in the SPRED1 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-38252854-G-A			Likely benign (Jun 26, 2018)
15-38252877-C-T		Legius syndrome	Uncertain significance (Jan 12, 2018)
15-38252891-CCT-C		RASopathy	Likely benign (May 23, 2019)
15-38252892-C-T		Legius syndrome	Uncertain significance (Jan 13, 2018)
15-38252942-T-C		Legius syndrome	Benign (Jan 12, 2018)
15-38252985-G-A		Legius syndrome	Uncertain significance (Jan 12, 2018)
15-38252995-C-T		Legius syndrome	Likely benign (Jan 13, 2018)
15-38253011-G-T		Legius syndrome	Uncertain significance (Jan 15, 2018)
15-38253023-TG-T		Legius syndrome	Likely benign (Jun 14, 2016)
15-38253034-C-A		Legius syndrome	Uncertain significance (Jan 13, 2018)
15-38253052-C-T			Uncertain significance (Mar 06, 2023)
15-38253072-G-A		Legius syndrome	Uncertain significance (Jan 13, 2018)
15-38253093-C-T		Legius syndrome • Noonan syndrome and Noonan-related syndrome	Benign (Jan 13, 2018)
15-38253099-C-T		Legius syndrome	Uncertain significance (Jan 12, 2018)
15-38253162-A-G		Legius syndrome	Uncertain significance (Jan 12, 2018)
15-38253164-A-C		not specified	Uncertain significance (Sep 12, 2016)
15-38253168-G-T			Uncertain significance (Jan 18, 2018)
15-38253174-G-C		not specified	Uncertain significance (Oct 15, 2019)
15-38253174-G-T		not specified	Uncertain significance (Aug 10, 2015)
15-38253184-A-T		Noonan syndrome and Noonan-related syndrome • Cardiovascular phenotype	Uncertain significance (May 05, 2021)
15-38253185-GAT-G		Legius syndrome	Likely pathogenic (Nov 01, 2016)
15-38253186-A-G		Legius syndrome	Pathogenic/Likely pathogenic (Sep 12, 2019)
15-38253188-G-A		Legius syndrome	Pathogenic (Aug 23, 2022)
15-38253190-GCGAGGAGACGGCGA-G		Legius syndrome	Pathogenic (Nov 01, 2016)
15-38253191-C-A		Legius syndrome • Cardiovascular phenotype	Uncertain significance (Nov 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPRED1	protein_coding	protein_coding	ENST00000299084	7	104924

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.972	0.0275	125728	0	6	125734	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.17	194	246	0.790	0.0000134	2956
Missense in Polyphen		58	85.539	0.67805		1032
Synonymous	1.42	66	82.3	0.801	0.00000460	785
Loss of Function	4.00	3	24.3	0.123	0.00000165	270

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000618	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tyrosine kinase substrate that inhibits growth-factor- mediated activation of MAP kinase. Negatively regulates hematopoiesis of bone marrow (By similarity). {ECO:0000250}.
• Disease: DISEASE: Neurofibromatosis 1-like syndrome (NFLS) [MIM:611431]: A disorder characterized mainly by cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1, axillary freckling, and macrocephaly. Additional clinical manifestations include Noonan-like facial dysmorphism, lipomas, learning disabilities and attention deficit-hyperactivity. {ECO:0000269|PubMed:17704776, ECO:0000269|PubMed:19443465, ECO:0000269|PubMed:20108422, ECO:0000269|PubMed:21089071}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: IL-5 Signaling Pathway;Regulation of Microtubule Cytoskeleton;Signal Transduction;Signaling by FGFR;Regulation of RAS by GAPs;KitReceptor;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Signaling by Receptor Tyrosine Kinases;Signaling events mediated by Stem cell factor receptor (c-Kit);FGFRL1 modulation of FGFR1 signaling;Signaling by FGFR1 (Consensus)

Recessive Scores

• pRec: 0.0921

Intolerance Scores

• loftool: 0.250
• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.37

Haploinsufficiency Scores

• pHI: 0.449
• hipred: Y
• hipred_score: 0.783
• ghis: 0.571

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.843

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Spred1
• Phenotype: growth/size/body region phenotype; craniofacial phenotype; hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; immune system phenotype; limbs/digits/tail 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)

Zebrafish Information Network

• Gene name: spred1
• Affected structure: thoracic duct
• Phenotype tag: abnormal
• Phenotype quality: hypoplastic

Gene ontology

• Biological process: MAPK cascade;inactivation of MAPK activity;negative regulation of protein kinase activity;fibroblast growth factor receptor signaling pathway;negative regulation of peptidyl-threonine phosphorylation;negative regulation of phosphatase activity;negative regulation of angiogenesis;regulation of MAPK cascade;negative regulation of MAPK cascade;positive regulation of DNA damage response, signal transduction by p53 class mediator;vasculogenesis involved in coronary vascular morphogenesis;negative regulation of ERK1 and ERK2 cascade;negative regulation of cell migration involved in sprouting angiogenesis;regulation of protein deacetylation
• Cellular component: nucleus;cytosol;plasma membrane;caveola;cytoplasmic vesicle
• Molecular function: stem cell factor receptor binding;protein binding;protein kinase binding;phosphatase binding;protein serine/threonine kinase inhibitor activity