FBLN1

protein-coding

fibulin 1, the group of Fibulins

Gene summary

Fibulin 1 is a secreted glycoprotein that becomes incorporated into a fibrillar extracellular matrix. Calcium-binding is apparently required to mediate its binding to laminin and nidogen. It mediates platelet adhesion via binding fibrinogen. Four splice variants which differ in the 3' end have been identified. Each variant encodes a different isoform, but no functional distinctions have been identified among the four variants. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006486.3

Inheritance

AD, AR

ClinVar variants

P:1U:148B:79

Top phenotype

Synpolydactyly 2

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr22:45,502,238-45,601,135

External References & Databases

Ensembl (ENSG00000077942)

Transcript & Mutation Effects

hg38 • Region Span ~98.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

synpolydactyly type 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011984

Submitter: PanelApp Australia

synpolydactyly type 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011984

Submitter: Labcorp Genetics (formerly Invitae)

FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018443

Submitter: Orphanet

synpolydactyly type 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011984

Submitter: PanelApp Australia

synpolydactyly type 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011984

Submitter: G2P

Clinical Genomic Database (CGD)

Synpolydactyly 2AD

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; In Cutis laxa, individuals can have cardiac manifestations such as supravalvular aortic stenosis, but the condition should be recognizable

Refs: 8831136; 11836357

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBLN1 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 154

not providedTotal: 149

FBLN1-related disorderTotal: 43

Synpolydactyly type 2Total: 7

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

Autosomal recessive syndrome of syndactyly, undescended testes and central nervous system defectsTotal: 1

Fetal akinesia deformation sequence 1Total: 1

Arthrogryposis multiplex congenitaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006486.3. 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			4 clinvar	55 clinvar	5 clinvar	64
missense		1 clinvar	138 clinvar	18 clinvar	1 clinvar	158
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	1	148	73	6	228

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006486.3	RefSeq	NP_006477.3	17	MANE Select
ENST00000327858.11	Ensembl	ENSP00000331544.6	17	MANE Select
NM_001996.4	RefSeq	NP_001987.3	15	Standard
NM_006485.4	RefSeq	NP_006476.3	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Extracellular matrix organization
Molecules associated with elastic fibres
Elastic fibre formation

Biological Process

negative regulation of protein phosphorylation
negative regulation of cell adhesion
integrin-mediated signaling pathway
embryo implantation
positive regulation of peptidase activity

Molecular Function

fibronectin binding
extracellular matrix structural constituent
calcium ion binding
protein C-terminus binding
peptidase activator activity

Cellular Component

extracellular region
basement membrane
extracellular space
extracellular matrix
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000327858
Coding exons: 17
Length: 98898
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.43	350	434	0.807	0.0000321	4633
Missense (PolyPhen)		128	158.76	0.80624		1532
Synonymous	-0.645	191	180	1.06	0.0000148	1325
Loss of Function	4.74	7	38.9	0.180	0.00000216	426

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	0.000058	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Incorporated into fibronectin-containing matrix fibers. May play a role in cell adhesion and migration along protein fibers within the extracellular matrix (ECM). Could be important for certain developmental processes and contribute to the supramolecular organization of ECM architecture, in particular to those of basement membranes. Has been implicated in a role in cellular transformation and tumor invasion, it appears to be a tumor suppressor. May play a role in haemostasis and thrombosis owing to its ability to bind fibrinogen and incorporate into clots. Could play a significant role in modulating the neurotrophic activities of APP, particularly soluble APP. {ECO:0000269|PubMed:11792823, ECO:0000269|PubMed:9393974, ECO:0000269|PubMed:9466671}.;
Disease: DISEASE: Note=A chromosomal aberration involving FBLN1 is found in a complex type of synpolydactyly referred to as 3/3-prime/4 synpolydactyly associated with metacarpal and metatarsal synostoses. Reciprocal translocation t(12;22)(p11.2;q13.3) with RASSF8. Fibroblasts derived from a patient with synpolydactyly displayed alterations in the level of isoform D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of isoform C was not perturbed in the patients fibroblasts. Furthermore, no aberrant polypeptides were detected in extracts of cultured patients fibroblasts. The translocation t(12;22) may result in haploinsufficiency of the isoform D splice variant, which could lead to the observed limb malformation. {ECO:0000269|PubMed:11836357}.; DISEASE: Note=Elevated expression and altered processing of FBLN1 protein is associated with human breast cancer. {ECO:0000269|PubMed:12644824}.;

Recessive Scores

pRec: 0.235

Intolerance Scores

LoFtool: 0.0203
RVIS EVS: -0.35
RVIS percentile EVS: 29.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.740

Gene Damage Prediction

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