ZP3

protein-coding

zona pellucida glycoprotein 3, 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 protein encoded by this gene is a structural component of the zona pellucida and functions in primary binding and induction of the sperm acrosome reaction. The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a C-terminal consensus furin cleavage site, and a 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. A variation in the last exon of this gene has previously served as the basis for an additional ZP3 locus; however, sequence and literature review reveals that there is only one full-length ZP3 locus in the human genome. Another locus encoding a bipartite transcript designated POMZP3 contains a duplication of the last four exons of ZP3, including the above described variation, and maps closely to this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

ZP3A
ZP3B

MANE transcript

NM_001110354.2

Inheritance

AD, AR

ClinVar variants

P:4U:84B:19

Top phenotype

Oocyte/zygote/embryo maturation arrest 3

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr7:76,397,518-76,442,071

External References & Databases

Ensembl (ENSG00000188372)

Transcript & Mutation Effects

hg38 • Region Span ~44.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oocyte maturation defect 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0021574

Submitter: Labcorp Genetics (formerly Invitae)

female infertility due to zona pellucida defectSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014342

Submitter: Orphanet

inherited oocyte maturation defectLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014769

Submitter: Ambry Genetics

oocyte maturation defect 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0021574

Submitter: PanelApp Australia

oocyte maturation defect 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0021574

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Oocyte/zygote/embryo maturation arrest 3AD

Manifestation: Obstetric

Intervention: General

Rationale: 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

Refs: 28886344

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZP3 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 80

not providedTotal: 18

Oocyte maturation defect 3Total: 8

ZP3-related disorderTotal: 3

Oocyte maturation defect 6Total: 1

Empty follicle syndromeTotal: 1

Empty ovarian follicleTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001110354.2. 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				5 clinvar	2 clinvar	7
missense	1 clinvar	1 clinvar	80 clinvar	7 clinvar	5 clinvar	94
nonsense						0
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)	1 clinvar		4 clinvar			5
Total	2	2	84	12	7	107

Highest pathogenic variant AF is 0.0000013682529

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001110354.2	RefSeq	NP_001103824.1	8	MANE Select
ENST00000394857.8	Ensembl	ENSP00000378326.3	8	MANE Select
NM_007155.6	RefSeq	NP_009086.4	8	Standard
ENST00000336517.8	Ensembl	ENSP00000337310.4	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ovarian Infertility Genes
Interaction With The Zona Pellucida
Fertilization
Reproduction

Biological Process

positive regulation of type IV hypersensitivity
blastocyst formation
humoral immune response mediated by circulating immunoglobulin
positive regulation of leukocyte migration
positive regulation of humoral immune response

Molecular Function

extracellular matrix structural constituent
protein binding
carbohydrate binding
acrosin binding
structural constituent of egg coat

Cellular Component

extracellular region
extracellular space
plasma membrane
integral component of membrane
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394857
Coding exons: 8
Length: 44554
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0164	240	239	1.00	0.0000132	2743
Missense (PolyPhen)		57	69.098	0.82492		875
Synonymous	-2.27	127	98.3	1.29	0.00000595	860
Loss of Function	1.70	8	15.2	0.528	7.02e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000052	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

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. ZP3 is essential for sperm binding and zona matrix formation.;
Disease: DISEASE: Oocyte maturation defect 3 (OOMD3) [MIM:617712]: An autosomal dominant infertility disorder characterized by abnormal oocytes that lack the zona pellucida, and oocytes degeneration. {ECO:0000269|PubMed:28886344}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.202

Intolerance Scores

LoFtool: 0.238
RVIS EVS: 0.78
RVIS percentile EVS: 87.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0208

Gene Damage Prediction

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