FEZF1

protein-coding

FEZ family zinc finger 1, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a transcriptional repressor that belongs to the zinc finger double domain protein family. The encoded protein is thought to play a role in the embryonic migration of gonadotropin-releasing hormone neurons into the brain. Mutations in this gene are associated with hypogonadotropic hypogonadism-22 with anosmia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

Previous symbols:

ZNF312B

MANE transcript

NM_001024613.4

Inheritance

AR, AD

ClinVar variants

P:2U:75B:28

Top phenotype

Hypogonadotropic hypogonadism 22 with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr7:122,301,303-122,310,691

External References & Databases

Ensembl (ENSG00000128610)

Transcript & Mutation Effects

hg38 • Region Span ~9.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 22 with or without anosmiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014461

Submitter: PanelApp Australia

hypogonadotropic hypogonadism 22 with or without anosmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014461

Submitter: G2P

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

hypogonadotropic hypogonadism 22 with or without anosmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014461

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadism 22 with or without anosmiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014461

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 22 with or without anosmiaAR

Manifestation: Endocrine; 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

Refs: 25192046

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FEZF1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 63

not providedTotal: 48

not specifiedTotal: 14

FEZF1-related disorderTotal: 10

Hypogonadotropic hypogonadism 22 with or without anosmiaTotal: 3

Hypogonadotropic hypogonadism 22 with anosmiaTotal: 2

Hypogonadotropic hypogonadism 7 with or without anosmiaTotal: 1

AmenorrheaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001024613.4. 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			1 clinvar	22 clinvar	1 clinvar	24
missense	1 clinvar		73 clinvar	5 clinvar		79
nonsense						0
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	2	0	75	27	1	105

Highest pathogenic variant AF is 6.8406564e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001024613.4	RefSeq	NP_001019784.2	4	MANE Select
ENST00000442488.7	Ensembl	ENSP00000411145.2	4	MANE Select
NM_001160264.2	RefSeq	NP_001153736.1	5	Standard
ENST00000418046.1	Ensembl	ENSP00000406919.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fezf1	Danio rerio	Structure: hypothalamus development Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

fezf1

Danio rerio

Structure: hypothalamus development

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Olfactory bulb development and olfactory learning

Biological Process

negative regulation of transcription by RNA polymerase II
neuron migration
axon guidance
negative regulation of cell population proliferation
olfactory bulb development

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
metal ion binding

Cellular Component

nucleus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000442488
Coding exons: 4
Length: 9298
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125748
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.29	210	270	0.779	0.0000121	3110
Missense (PolyPhen)		63	102.02	0.61755		1263
Synonymous	0.162	113	115	0.981	0.00000548	957
Loss of Function	3.20	1	13.9	0.0722	6.07e-7	176

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	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000026	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription repressor. Involved in the axonal projection and proper termination of olfactory sensory neurons (OSN). Plays a role in rostro-caudal patterning of the diencephalon and in prethalamic formation. Expression is required in OSN to cell-autonomously regulate OSN axon projections. Regulates non-cell-autonomously the layer formation of the olfactory bulb development and the interneurons. May be required for correct rostral migration of the interneuron progenitors (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.0948

Intolerance Scores

LoFtool: 0.395
RVIS EVS: -0.01
RVIS percentile EVS: 53.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.887

Gene Damage Prediction

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