ZP4

protein-coding

zona pellucida glycoprotein 4, the group of Zona pellucida glycoproteins

Gene summary

The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a consensus furin cleavage site, and a C-terminal transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies. Previously, this gene has been referred to as ZP1 or ZPB and thought to have similar functions as mouse Zp1. However, a human gene with higher similarity and chromosomal synteny to mouse Zp1 has been assigned the symbol ZP1 and this gene has been assigned the symbol ZP4. [provided by RefSeq, Jul 2008]

MANE transcript

NM_021186.5

Inheritance

—

ClinVar variants

U:83B:17

Top phenotype

Prostate cancer

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr1:237,877,864-237,890,922

External References & Databases

Ensembl (ENSG00000116996)

Transcript & Mutation Effects

hg38 • Region Span ~13.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZP4 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 95

not providedTotal: 5

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021186.5. 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				2 clinvar		2
missense			83 clinvar	11 clinvar	4 clinvar	98
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	83	13	4	100

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021186.5	RefSeq	NP_067009.1	12	MANE Select
ENST00000366570.5	Ensembl	ENSP00000355529.4	12	MANE Select
ENST00000611898.4	Ensembl	ENSP00000482304.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Interaction With The Zona Pellucida
Fertilization
Reproduction

Biological Process

positive regulation of humoral immune response
binding of sperm to zona pellucida
positive regulation of T cell proliferation
acrosomal vesicle exocytosis
positive regulation of acrosome reaction

Molecular Function

protein binding
acrosin binding
identical protein binding

Cellular Component

extracellular region
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366570
Coding exons: 12
Length: 8390
Individuals with no LoFs: 125438
Homozygous LoFs: 0
Heterozygous LoFs: 310
Defined: 125748
p: 0.00123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.24	357	297	1.20	0.0000154	3496
Missense (PolyPhen)		83	79.429	1.045		989
Synonymous	-1.60	137	115	1.19	0.00000630	1098
Loss of Function	0.207	28	29.2	0.959	0.00000173	288

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0049	0.0049	notable
Latino/Admixed American	0.0020	0.0020	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0033	0.0020	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00070	0.00069	rare
South Asian	0.0013	0.0013	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The mammalian zona pellucida, which mediates species- specific sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy, is composed of three to four glycoproteins, ZP1, ZP2, ZP3, and ZP4. ZP4 may act as a sperm receptor.;

Recessive Scores

pRec: 0.178

Intolerance Scores

LoFtool: 0.451
RVIS EVS: -0.11
RVIS percentile EVS: 45.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.292

Gene Damage Prediction

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