FGB

protein-coding

fibrinogen beta chain, the group of Receptor ligands|Fibrinogen C domain containing

Gene summary

The protein encoded by this gene is the beta component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of nonidentical polypeptide chains. Following vascular injury, fibrinogen is cleaved by thrombin to form fibrin which is the most abundant component of blood clots. In addition, various cleavage products of fibrinogen and fibrin regulate cell adhesion and spreading, display vasoconstrictor and chemotactic activities, and are mitogens for several cell types. Fibrinogen serves key roles in hemostasis and antimicrobial host defense. Mutations in this gene lead to several disorders, including afibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia and thrombotic tendency. [provided by RefSeq, Aug 2020]

MANE transcript

NM_005141.5

Inheritance

AR, SD, AD

ClinVar variants

P:26U:128B:39

Top phenotype

Afibrinogenemia, congenital; Dysfibrinogenemia, congenital; Hypodysfibrinogenemia, congenital

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr4:154,563,011-154,572,807

External References & Databases

Ensembl (ENSG00000171564)

Transcript & Mutation Effects

hg38 • Region Span ~9.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital afibrinogenemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008737

Submitter: Orphanet

congenital fibrinogen deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0018060

Submitter: ClinGen

The relationship between FGB and congenital fibrinogen deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. More than a 30 pathogenic variants in this gene are reported in humans, ranging from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital fibrinogen deficiency is characterized by quantitative and qualitative defects in fibrinogen. It may manifest as afibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia. Clinical symptoms include a bleeding diathesis and/or a thrombotic phenotype. Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 8 publications (PMID: 23266225, 25629419, 24560896, 15070683, 12893758, 12161363, 23560673, 12511408). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease have been reported to be heterozygous as well as biallelic loss of function (PMID: 23266225, PMID:15070683). Summary of Experimental Data (3 points): FGB encodes the β subunit of the coagulation factor, fibrinogen, which is a hexamer of three subunit chains (PMID: 22836683). The Bβ fibrinopeptide along with Aα fibrinopeptide interact with thrombin, which catalyzes the conversion of fibrinogen to fibrin (PMID: 15572239). It is synthesized in the liver and secreted into the plasma (PMID: 20921339). A zebrafish model that recapitulate fibrinogen deficiency is reported (PMID: 24098662). In summary, the FGB-Congenital fibrinogen deficiency gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on January 22, 2020. (SOP Version 7) Lumping & Splitting information: OMIM assertions - (1) Congenital Afibrinogenemia (MIM: 202400); (2) Congenital Dysfibrinogenemia (MIM: 616004); (3) Congenital Hypofibrinogenemia (MIM: 202400). Orphanet assertions - (1) Familial afibrinogenemia; (2) Familial dysfibrinogenemia; (3) Familial hypodysfibrinogenemia; (4) Familial hypofibrinogenemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: Congenital Afibrinogenemia, Congenital Dysfibrinogenemia, Congenital Hypodysfibrinogenemia and Congenital Hypofibrinogenemia. These entities have been lumped together under Congenital Fibrinogen Deficiency.

familial hypofibrinogenemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015096

Submitter: Orphanet

congenital fibrinogen deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0018060

Submitter: PanelApp Australia

congenital afibrinogenemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008737

Submitter: Labcorp Genetics (formerly Invitae)

thrombophiliaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0002305

Submitter: Genomics England PanelApp

thrombophiliaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0002305

Submitter: Genomics England PanelApp

familial dysfibrinogenemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014452

Submitter: Orphanet

Clinical Genomic Database (CGD)

Afibrinogenemia, congenital; Dysfibrinogenemia, congenital; Hypodysfibrinogenemia, congenitalAD/AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals with afibrinogenemia/dysfibrinogenemia are at risk of a variety of bleeding diatheses; Preventive or treatment-based (eg, with fibrinogen in the case of congenital afibrinogenemia) may be beneficial

Refs: 3156856; 2885451; 3388290; 2018836; 1565641; 1634610; 9185528; 10666208; 11468164; 11425767; 12393540; 15070683; 18853456; 21301788; 22955321

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FGB variants in ClinVar

22 Conditions Cataloged

not providedTotal: 103

Inborn genetic diseasesTotal: 60

Congenital afibrinogenemiaTotal: 44

not specifiedTotal: 40

FGB-related disorderTotal: 31

Familial dysfibrinogenemiaTotal: 16

HypofibrinogenemiaTotal: 5

Abnormal bleedingTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005141.5. 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			4 clinvar	25 clinvar	3 clinvar	32
missense	5 clinvar	6 clinvar	122 clinvar	11 clinvar		144
nonsense	2 clinvar	2 clinvar	1 clinvar			5
start loss						0
frameshift	1 clinvar	7 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar				3
Total	9	17	128	36	3	193

Highest pathogenic variant AF is 0.000081157166

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005141.5	RefSeq	NP_005132.2	8	MANE Select
ENST00000302068.9	Ensembl	ENSP00000306099.4	8	MANE Select
NM_001184741.1	RefSeq	NP_001171670.1	8	Standard
NM_001382759.1	RefSeq	NP_001369688.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
Aminocaproic Acid Action Pathway
Tranexamic Acid Action Pathway

Biological Process

toll-like receptor signaling pathway
adaptive immune response
platelet degranulation
cell-matrix adhesion
blood coagulation

Molecular Function

signaling receptor binding
structural molecule activity
extracellular matrix structural constituent
protein binding
cell adhesion molecule binding

Cellular Component

extracellular region
fibrinogen complex
extracellular space
endoplasmic reticulum
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302068
Coding exons: 8
Length: 8131
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.732	231	264	0.873	0.0000136	3254
Missense (PolyPhen)		66	104.81	0.62969		1174
Synonymous	-0.719	99	90.3	1.10	0.00000483	862
Loss of Function	3.63	5	24.3	0.206	0.00000110	304

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways. {ECO:0000250|UniProtKB:E9PV24}.;
Disease: DISEASE: Congenital afibrinogenemia (CAFBN) [MIM:202400]: Rare autosomal recessive disorder is characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. {ECO:0000269|PubMed:10666208, ECO:0000269|PubMed:11468164, ECO:0000269|PubMed:15070683, ECO:0000269|PubMed:25427968}. Note=The disease is caused by mutations affecting the gene represented in this entry. Patients with congenital fibrinogen abnormalities can manifest different clinical pictures. Some cases are clinically silent, some show a tendency toward bleeding and some show a predisposition for thrombosis with or without bleeding.; DISEASE: Dysfibrinogenemia, congenital (DYSFIBRIN) [MIM:616004]: A disorder characterized by qualitative abnormalities (dysfibrinogenemia) of the circulating fibrinogen. Affected individuals are frequently asymptomatic, but some patients have bleeding diathesis, thromboembolic complications, or both. In some cases, dysfibrinogenemia is associated with low circulating fibrinogen levels (hypodysfibrinogenemia). {ECO:0000269|PubMed:1634610}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.411

Intolerance Scores

LoFtool: 0.194
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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