SPRY4

sprouty RTK signaling antagonist 4

Basic information

Region (hg38): 5:142310426-142326455

Links

ENSG00000187678 ∙ NCBI:81848 ∙ OMIM:607984 ∙ HGNC:15533 ∙ Uniprot:Q9C004 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism 17 with or without anosmia (Limited), mode of inheritance: AD
• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 17 with or without anosmia (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 17, with or without anosmia	AD/Digenic	Endocrine	In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required	Audiologic/Otolaryngologic; Dental; Endocrine; Musculoskeletal; Neurologic	23643382
Relatively complex genetic models of disease have been described (eg, involving variants in other FGF8-network-associated genes)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPRY4 gene.

• not provided (40 variants)
• Inborn genetic diseases (14 variants)
• Hypogonadotropic hypogonadism 17 with or without anosmia (3 variants)
• Hypogonadotropic hypogonadism (1 variants)
• not specified (1 variants)
• SPRY4-related condition (1 variants)
• Amenorrhea (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPRY4 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				13		13
missense			30	4	1	35
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding					4	4
Total	0	0	30	17	5

Variants in SPRY4

This is a list of pathogenic ClinVar variants found in the SPRY4 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-142314028-C-T			Benign (Aug 09, 2018)
5-142314111-C-G			Benign (Nov 27, 2018)
5-142314217-G-C			Uncertain significance (Feb 14, 2023)
5-142314223-C-T			Uncertain significance (Apr 17, 2023)
5-142314224-G-A			Likely benign (Dec 01, 2023)
5-142314231-C-T			Uncertain significance (Aug 27, 2023)
5-142314247-C-T		not specified	Uncertain significance (Mar 21, 2023)
5-142314264-A-G		not specified	Uncertain significance (Apr 08, 2022)
5-142314268-C-T		Hypogonadotropic hypogonadism 17 with or without anosmia	Benign (Dec 24, 2023)
5-142314277-T-C		not specified	Uncertain significance (Aug 08, 2022)
5-142314290-G-C			Uncertain significance (Oct 20, 2022)
5-142314309-C-T			Uncertain significance (Nov 13, 2023)
5-142314321-C-T		not specified	Uncertain significance (Jun 12, 2023)
5-142314331-G-T		Disorder of sexual differentiation	Uncertain significance (Aug 17, 2021)
5-142314337-C-T		SPRY4-related disorder	Conflicting classifications of pathogenicity (Dec 28, 2023)
5-142314382-C-T		not specified	Uncertain significance (Jul 30, 2023)
5-142314383-G-A			Likely benign (Jul 17, 2023)
5-142314412-C-T			Uncertain significance (Dec 20, 2023)
5-142314413-G-A			Likely benign (Nov 09, 2021)
5-142314427-G-A		not specified	Uncertain significance (Jun 29, 2023)
5-142314443-G-A			Likely benign (Jul 07, 2023)
5-142314451-C-T			Uncertain significance (Aug 16, 2022)
5-142314452-G-A			Likely benign (Dec 09, 2023)
5-142314456-G-T		Hypogonadotropic hypogonadism 17 with or without anosmia • not specified • Amenorrhea	Conflicting classifications of pathogenicity (Jan 22, 2024)
5-142314466-C-T		not specified	Uncertain significance (Mar 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPRY4	protein_coding	protein_coding	ENST00000344120	2	16029

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000482	0.691	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.503	198	219	0.904	0.0000146	2094
Missense in Polyphen		80	94.079	0.85035		982
Synonymous	-0.436	99	93.6	1.06	0.00000651	675
Loss of Function	0.814	6	8.57	0.700	3.69e-7	98

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000165	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.000168	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.00000913	0.00000879
Middle Eastern	0.000168	0.000163
South Asian	0.0000655	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1. {ECO:0000269|PubMed:12717443}.
• Disease: DISEASE: Hypogonadotropic hypogonadism 17 with or without anosmia (HH17) [MIM:615266]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in SPRY4 also have a heterozygous mutation in another HH-associated gene including DUSP6 and FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
• Pathway: sprouty regulation of tyrosine kinase signals;EGFR1 (Consensus)

Recessive Scores

• pRec: 0.142

Intolerance Scores

• loftool: 0.571
• rvis_EVS: -0.05
• rvis_percentile_EVS: 50.34

Haploinsufficiency Scores

• pHI: 0.930
• hipred: Y
• hipred_score: 0.525
• ghis: 0.508

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.942

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Spry4
• 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); limbs/digits/tail phenotype; vision/eye phenotype; skeleton phenotype; respiratory 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); craniofacial phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: spry4
• Affected structure: blood cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: multicellular organism development;negative regulation of fibroblast growth factor receptor signaling pathway;negative regulation of MAP kinase activity;negative regulation of Ras protein signal transduction;negative regulation of ERK1 and ERK2 cascade
• Cellular component: cytosol;focal adhesion;ruffle membrane
• Molecular function: protein binding