PROZ

protein-coding

protein Z, vitamin K dependent plasma glycoprotein, the group of Gla domain containing

Gene summary

This gene encodes a liver vitamin K-dependent glycoprotein that is synthesized in the liver and secreted into the plasma. The encoded protein plays a role in regulating blood coagulation by complexing with protein Z-dependent protease inhibitor to directly inhibit activated factor X at the phospholipid surface. Deficiencies in this protein are associated with an increased risk of ischemic arterial diseases and fetal loss. Mutations in this gene are the cause of protein Z deficiency. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

MANE transcript

NM_003891.3

Inheritance

ClinVar variants

U:77B:19

Top phenotype

Protein Z deficiency

gnomAD constraint

pLI —, LoF o/e 1.23

Max pathogenic AF

—

Genomic locus

chr13:113,158,648-113,172,386

External References & Databases

Ensembl (ENSG00000126231)

Transcript & Mutation Effects

hg38 • Region Span ~13.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

protein Z deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013532

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Protein Z deficiencyAD

Manifestation: General

Intervention: General

Rationale: There is weak or mixed evidence that protein Z deficiency has an adverse health effect

Refs: 7495103; 10829076; 11289354; 11895801; 15638861; 14671240; 15626740; 16938126; 20076855

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PROZ variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 85

not providedTotal: 7

Protein Z deficiencyTotal: 5

PROZ-related disorderTotal: 3

ThrombocytopeniaTotal: 1

Abnormal bleedingTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003891.3. 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	3 clinvar	8
missense			76 clinvar	9 clinvar	1 clinvar	86
nonsense						0
start loss						0
frameshift			1 clinvar	1 clinvar		2
splice donor/acceptor (+/-2bp)						0
Total	0	0	77	15	4	96

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003891.3	RefSeq	NP_003882.1	8	MANE Select
ENST00000375547.7	Ensembl	ENSP00000364697.2	8	MANE Select
NM_001256134.2	RefSeq	NP_001243063.1	9	Standard
ENST00000342783.5	Ensembl	ENSP00000344458.4	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Warfarin Pathway, Pharmacodynamics
Post-translational protein modification
Metabolism of proteins
Gamma-carboxylation of protein precursors
Removal of aminoterminal propeptides from gamma-carboxylated proteins

Biological Process

proteolysis
endoplasmic reticulum to Golgi vesicle-mediated transport
blood coagulation

Molecular Function

serine-type endopeptidase activity
calcium ion binding

Cellular Component

extracellular space
endoplasmic reticulum lumen
Golgi lumen
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342783
Coding exons: 9
Length: 13727
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0555	257	255	1.01	0.0000156	2727
Missense (PolyPhen)		84	88.044	0.95407		1032
Synonymous	0.380	101	106	0.953	0.00000742	826
Loss of Function	-0.900	22	17.9	1.23	9.65e-7	197

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Appears to assist hemostasis by binding thrombin and promoting its association with phospholipid vesicles. Inhibits activity of the coagulation protease factor Xa in the presence of SERPINA10, calcium and phospholipids.;

Recessive Scores

pRec: 0.257

Intolerance Scores

LoFtool: 0.261
RVIS EVS: -0.24
RVIS percentile EVS: 36.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.310

Gene Damage Prediction

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