FGF17

protein-coding

fibroblast growth factor 17, the group of Fibroblast growth factor family

Gene summary

This gene encodes a member of the fibroblast growth factor (FGF) family. Member of the FGF family possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein is expressed during embryogenesis and in the adult cerebellum and cortex and may be essential for vascular growth and normal brain development. Mutations in this gene are the cause of hypogonadotropic hypogonadism 20 with or without anosmia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

MANE transcript

NM_003867.4

Inheritance

AD, Multigenic

ClinVar variants

P:1U:30B:17

Top phenotype

Hypogonadotropic hypogonadism 20, with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr8:22,042,398-22,048,809

External References & Databases

Ensembl (ENSG00000158815)

Transcript & Mutation Effects

hg38 • Region Span ~6.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 20 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014106

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Orphanet

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

hypogonadotropic hypogonadism 20 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014106

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 20, with or without anosmiaAD/Multigenic

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: 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

Comments: Relatively complex genetic models of disease have been described (eg, involving variants in other FGF8-network-associated genes)

Refs: 6881209; 23643382

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FGF17 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 41

not specifiedTotal: 20

FGF17-related disorderTotal: 4

Hypogonadotropic hypogonadism 20 with or without anosmiaTotal: 3

Hypogonadotropic hypogonadism 20 without anosmiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003867.4. 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				14 clinvar	2 clinvar	16
missense	1 clinvar		28 clinvar	1 clinvar		30
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	0	30	15	2	48

Highest pathogenic variant AF is 0.0000013688542

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003867.4	RefSeq	NP_003858.1	5	MANE Select
ENST00000359441.4	Ensembl	ENSP00000352414.3	5	MANE Select
NM_001304478.1	RefSeq	NP_001291407.1	5	Standard
ENST00000518533.5	Ensembl	ENSP00000431041.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Gastric cancer - Homo sapiens (human)
Melanoma - Homo sapiens (human)
Breast cancer - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

MAPK cascade
signal transduction
cell-cell signaling
nervous system development
positive regulation of cell population proliferation

Molecular Function

protein tyrosine kinase activity
Ras guanyl-nucleotide exchange factor activity
type 1 fibroblast growth factor receptor binding
type 2 fibroblast growth factor receptor binding
growth factor activity

Cellular Component

extracellular region
extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359441
Coding exons: 5
Length: 6412
Individuals with no LoFs: 125574
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125577
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.85	89	154	0.579	0.0000101	1416
Missense (PolyPhen)		18	61.693	0.29177		519
Synonymous	-0.207	65	62.9	1.03	0.00000418	419
Loss of Function	2.90	0	9.79	0.00	4.17e-7	110

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
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)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the regulation of embryonic development and as signaling molecule in the induction and patterning of the embryonic brain. Required for normal brain development. {ECO:0000269|PubMed:16597617}.;
Disease: DISEASE: Hypogonadotropic hypogonadism 20 with or without anosmia (HH20) [MIM:615270]: 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 FGF17 also have a mutation in another HH-associated gene including FGFR1, HS6ST1 and FLRT3 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.0960
RVIS EVS: -0.23
RVIS percentile EVS: 36.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.394

Gene Damage Prediction

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