PCSK4

protein-coding

proprotein convertase subtilisin/kexin type 4, the group of Proprotein convertase subtilisin/kexin family

Gene summary

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]

MANE transcript

NM_017573.5

Inheritance

—

ClinVar variants

U:169B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr19:1,481,428-1,490,752

External References & Databases

Ensembl (ENSG00000115257)

Transcript & Mutation Effects

hg38 • Region Span ~9.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCSK4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 171

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017573.5. 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 clinvar		4
missense			164 clinvar	7 clinvar	1 clinvar	172
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	169	9	1	179

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017573.5	RefSeq	NP_060043.2	15	MANE Select
ENST00000300954.10	Ensembl	ENSP00000300954.5	15	MANE Select
NM_001395257.1	RefSeq	NP_001382186.1	14	Standard
ENST00000588671.2	Ensembl	ENSP00000466742.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

binding of sperm to zona pellucida
acrosome reaction
fertilization
protein processing
peptide hormone processing

Molecular Function

serine-type endopeptidase activity
protein binding

Cellular Component

acrosomal vesicle
acrosomal membrane
trans-Golgi network
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300954
Coding exons: 15
Length: 9325
Individuals with no LoFs: 125638
Homozygous LoFs: 1
Heterozygous LoFs: 89
Defined: 125728
p: 0.000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0360	497	495	1.00	0.0000348	4728
Missense (PolyPhen)		195	201.61	0.96722		1936
Synonymous	-1.76	267	233	1.15	0.0000186	1568
Loss of Function	1.73	24	35.0	0.685	0.00000188	335

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00079	0.00074	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.0029	0.0028	notable
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00031	0.00028	rare
South Asian	0.00030	0.00029	rare
Other	0.00035	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Proprotein convertase involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues (By similarity). In males, important for ADAM2 processing as well as other acrosomal proteins with roles in fertilization and critical for normal fertilization events such as sperm capacitation, acrosome reaction and binding of sperm to zona pellucida (By similarity). Plays also a role in female fertility, involved in the regulation of trophoblast migration and placental development, may be through the proteolytical processing and activation of proteins such as IGF2 (PubMed:16040806). May also participate in folliculogenesis in the ovaries (By similarity). {ECO:0000250|UniProtKB:P29121, ECO:0000269|PubMed:16040806}.;

Recessive Scores

pRec: 0.129

Intolerance Scores

LoFtool: 0.235
RVIS EVS: 0.61
RVIS percentile EVS: 82.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.368

Gene Damage Prediction

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