SERPINF1

protein-coding

serpin family F member 1, the group of Serpin peptidase inhibitors

Gene summary

This gene encodes a member of the serpin family that does not display the serine protease inhibitory activity shown by many of the other serpin proteins. The encoded protein is secreted and strongly inhibits angiogenesis. In addition, this protein is a neurotrophic factor involved in neuronal differentiation in retinoblastoma cells. Mutations in this gene were found in individuals with osteogenesis imperfecta, type VI. [provided by RefSeq, Aug 2016]

Previous symbols:

PEDF

MANE transcript

NM_002615.7

Inheritance

AR, AD

ClinVar variants

P:62U:135B:124

Top phenotype

Osteogenesis imperfecta, type VI

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr17:1,762,029-1,777,565

External References & Databases

Ensembl (ENSG00000132386)

Transcript & Mutation Effects

hg38 • Region Span ~15.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteogenesis imperfecta type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013515

Submitter: Labcorp Genetics (formerly Invitae)

osteogenesis imperfecta type 4SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008148

Submitter: Orphanet

osteogenesis imperfecta type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013515

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

osteogenesis imperfecta type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009804

Submitter: Orphanet

osteogenesis imperfecta type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013515

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Osteogenesis imperfecta, type VIAR

Manifestation: Musculoskeletal

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

Comments: Bisphosphonates may reduce fracture frequency, and use of RANKL antibody has been described as potentially beneficial

Refs: 11771667; 17127117; 21353196; 21826736; 22947550; 23613367

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINF1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 289

Osteogenesis imperfecta type 6Total: 84

Inborn genetic diseasesTotal: 62

not specifiedTotal: 50

SERPINF1-related disorderTotal: 28

Osteogenesis imperfectaTotal: 23

Osteogenesis imperfecta type IIITotal: 3

OsteoporosisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002615.7. 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	105 clinvar		109
missense		3 clinvar	127 clinvar	16 clinvar	3 clinvar	149
nonsense	14 clinvar	7 clinvar				21
start loss						0
frameshift	19 clinvar	10 clinvar	2 clinvar			31
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	2 clinvar			11
Total	36	26	135	121	3	321

Highest pathogenic variant AF is 0.000030355444

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002615.7	RefSeq	NP_002606.3	7	MANE Select
ENST00000254722.9	Ensembl	ENSP00000254722.4	7	MANE Select
NM_001329903.2	RefSeq	NP_001316832.1	7	Standard
NM_001329904.2	RefSeq	NP_001316833.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Wnt signaling pathway - Homo sapiens (human)
Wnt Signaling Pathway

Biological Process

kidney development
multicellular organism development
aging
short-term memory
cell population proliferation

Molecular Function

serine-type endopeptidase inhibitor activity
protein binding

Cellular Component

extracellular region
basement membrane
extracellular space
melanosome
axon hillock

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000254722
Coding exons: 7
Length: 15616
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125747
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.911	275	236	1.17	0.0000142	2714
Missense (PolyPhen)		88	80.507	1.0931		931
Synonymous	-2.31	136	106	1.29	0.00000699	866
Loss of Function	0.904	13	17.0	0.764	9.51e-7	197

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells. Potent inhibitor of angiogenesis. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity. {ECO:0000269|PubMed:7592790, ECO:0000269|PubMed:8226833}.;
Disease: DISEASE: Osteogenesis imperfecta 6 (OI6) [MIM:613982]: A form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI6 is a severe, autosomal recessive form compatible with OI type III in the Sillence classification. {ECO:0000269|PubMed:21353196}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.283
RVIS EVS: -0.6
RVIS percentile EVS: 18.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.152

Gene Damage Prediction

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