PCSK7

protein-coding

proprotein convertase subtilisin/kexin type 7, 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. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event 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. It can process proalbumin and is thought to be responsible for the activation of HIV envelope glycoproteins gp160 and gp140. This gene has been implicated in the transcriptional regulation of housekeeping genes and plays a role in the regulation of iron metabolism. A t(11;14)(q23;q32) chromosome translocation associated with B-cell lymphoma occurs between this gene and its inverted counterpart. [provided by RefSeq, Feb 2014]

MANE transcript

NM_004716.4

Inheritance

—

ClinVar variants

U:119B:8

Top phenotype

Skin tags

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr11:117,204,337-117,232,525

External References & Databases

Ensembl (ENSG00000160613)

Transcript & Mutation Effects

hg38 • Region Span ~28.2 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 PCSK7 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 102

not providedTotal: 8

Skin tagsTotal: 2

Pericallosal lipomaTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Midline facial cleftTotal: 1

Hereditary breast ovarian cancer syndromeTotal: 1

Preauricular skin tagTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004716.4. 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			4 clinvar	4 clinvar		8
missense			106 clinvar	3 clinvar		109
nonsense			1 clinvar	1 clinvar		2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	119	8	0	127

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004716.4	RefSeq	NP_004707.2	15	MANE Select
ENST00000320934.8	Ensembl	ENSP00000325917.3	15	MANE Select
ENST00000524507.6	Ensembl	ENSP00000433841.2	15	Standard
ENST00000525027.1	Ensembl	ENSP00000431181.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pcsk7	Danio rerio	Structure: otolith Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

pcsk7

Danio rerio

Structure: otolith

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein processing
peptide hormone processing

Molecular Function

serine-type endopeptidase activity
peptidase activity

Cellular Component

trans-Golgi network
membrane
integral component of Golgi membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320934
Coding exons: 15
Length: 28189
Individuals with no LoFs: 125425
Homozygous LoFs: 0
Heterozygous LoFs: 323
Defined: 125748
p: 0.00129

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.49	373	463	0.806	0.0000282	5079
Missense (PolyPhen)		133	205.01	0.64874		2117
Synonymous	0.378	178	185	0.965	0.0000118	1542
Loss of Function	3.80	11	35.4	0.311	0.00000180	392

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00051	0.00049	rare
Latino/Admixed American	0.0011	0.0011	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00095	0.00092	rare
Finnish	0.00061	0.00060	rare
European (Non-Finnish)	0.0019	0.0019	notable
South Asian	0.00063	0.00062	rare
Other	0.0018	0.0018	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive secretory pathway.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.358
RVIS EVS: -0.75
RVIS percentile EVS: 13.67

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.204

Gene Damage Prediction

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