FLNB

protein-coding

filamin B, the group of Filamins

Gene summary

This gene encodes a member of the filamin family. The encoded protein interacts with glycoprotein Ib alpha as part of the process to repair vascular injuries. The platelet glycoprotein Ib complex includes glycoprotein Ib alpha, and it binds the actin cytoskeleton. Mutations in this gene have been found in several conditions: atelosteogenesis type 1 and type 3; boomerang dysplasia; autosomal dominant Larsen syndrome; and spondylocarpotarsal synostosis syndrome. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Nov 2009]

Previous symbols:

FLN1L
LRS1

MANE transcript

NM_001457.4

Inheritance

AD, AR

ClinVar variants

P:173U:1197B:936

Top phenotype

Larsen syndrome; Spondylocarpotarsal synostosis syndrome

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr3:58,008,398-58,172,251

External References & Databases

Ensembl (ENSG00000136068)

Transcript & Mutation Effects

hg38 • Region Span ~163.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

atelosteogenesis type IIIDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007168

Submitter: G2P

Larsen syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007875

Submitter: Labcorp Genetics (formerly Invitae)

spondylocarpotarsal synostosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010094

Submitter: Labcorp Genetics (formerly Invitae)

Boomerang dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007208

Submitter: Labcorp Genetics (formerly Invitae)

atelosteogenesis type ISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007167

Submitter: Orphanet

filamin-related bone disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019690

Submitter: PanelApp Australia

spondylocarpotarsal synostosis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010094

Submitter: G2P

spondylocarpotarsal synostosis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010094

Submitter: Orphanet

spondylocarpotarsal synostosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010094

Submitter: PanelApp Australia

FLNB-associated autosomal dominant filamin related bone disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1060173

Submitter: ClinGen

Filamin B (FLNB; MIM#603381) is a large dimeric actin binding protein and multi-functional signaling scaffold with roles in crosslinking actin cytoskeleton filaments, and signaling through interactions with a variety of receptors, signaling molecules, and transcription factors. FLNB is associated with both autosomal dominant and autosomal recessive disease entities with opposing mechanisms of disease. Given the difference in inheritance pattern and disease mechanism, the Prenatal Gene Curation Expert Panel has split these two disease entities into FLNB-associated autosomal dominant filamin related bone disorder(MONDO:1060173) and Spondylocarpotarsal Synostosis Syndrome (MONDO:0010094), inherited in an autosomal recessive pattern. These have been curated separately. Heterozygous variants in the FLNB gene were first reported in relation to a skeletal dysplasia in Krakow, et.al. 2004 [PMID:14991055] and since have been reported in many affected individuals with a wide phenotypic spectrum ranging from pre- or perinatal lethal skeletal dysplasia historically referred to as Boomerang Dysplasia to a milder form with survival to adulthood often referred to as Larsen syndrome, as well as intermediate phenotypes Atelosteogenesis Type I and Atelosteogenesis Type III. The Prenatal Gene Curation Expert Panel has found no evidence of different inheritance patterns or disease mechanism between these entities, with several recurrent variants or variants at the same amino acid associated with variable phenotypic presentations and severity (p.Met202, p.Gly1691Ser, p.Trp189Arg). Given this, the Prenatal Gene Curation Expert Panel has lumped these into a single disease entity, FLNB-associated autosomal dominant filamin related bone disorder (MONDO:1060173). Prenatal phenotypes are highly variable and include prenatal or perinatal lethality, hydrops or cystic hygroma, phocomelia, micromelia or absent bones of the limbs in the severe form of disease; and short limb dwarfism, club feet, polyhydramnios, congenital joint dislocations, fetal growth restriction, and dysmorphic features including micrognathia, cleft palate, hypertelorism and hypoplastic vertebrae in more mild presentations. Maximum genetic evidence was reached with both recurrent and non-recurrent variants, often identified de novo in affected individuals or inherited from variably affected parents [PMID:16752402, 2219045, 16801345, 19085972, 14991055, 22354125, others]. Genetic evidence is supported by functional evidence including protein-protein interactions, expression studies, and functional alterations demonstrating focal accumulations of FLNB with actin [PMID:11807098, 28175289, 17360453, 17635842, 17510210, 14991055, 22190451]. The mechanism of disease is proposed to be gain-of-function or dominant negative, and while missense and in-frame indel variants associated with milder phenotypic manifestations are found throughout the protein, variants found in the CH2 domain are more commonly associated with phenotypes on the more severe end of the spectrum [PMID:22190451]. In summary the Prenatal Gene Curation Expert Panel has found sufficient genetic and functional evidence to classify FLNB as DEFINITIVE for FLNB-associated autosomal dominant filamin related bone disorder (Gene-Disease Validity SOPv11).

atelosteogenesis type IIISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007168

Submitter: Orphanet

Larsen syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007875

Submitter: G2P

Larsen syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007875

Submitter: Orphanet

atelosteogenesis type IDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007167

Submitter: G2P

atelosteogenesis type ISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007167

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Larsen syndrome; Spondylocarpotarsal synostosis syndromeAD/AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Musculoskeletal

Intervention: Audiologic/Otolaryngologic; Musculoskeletal

Rationale: Surveillance and early intervention related to cervical spine stability can allow early detection and treatment of manifestations; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 8609132; 12955767; 14991055; 15994868; 17202879; 16801345; 18257094; 18377309; 18386804; 20301736; 22190451; 22354125

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FLNB variants in ClinVar

23 Conditions Cataloged

not providedTotal: 2464

Inborn genetic diseasesTotal: 371

not specifiedTotal: 275

FLNB-Related Spectrum DisordersTotal: 192

FLNB-related disorderTotal: 175

Larsen syndromeTotal: 122

Spondylocarpotarsal synostosis syndromeTotal: 112

Atelosteogenesis type ITotal: 91

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001457.4. 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			22 clinvar	582 clinvar	9 clinvar	613
missense	20 clinvar	41 clinvar	1150 clinvar	328 clinvar	17 clinvar	1556
nonsense	23 clinvar	11 clinvar	3 clinvar			37
start loss						0
frameshift	31 clinvar	18 clinvar	3 clinvar			52
splice donor/acceptor (+/-2bp)	3 clinvar	26 clinvar	19 clinvar			48
Total	77	96	1197	910	26	2306

Highest pathogenic variant AF is 0.00026150807

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001457.4	RefSeq	NP_001448.2	46	MANE Select
ENST00000295956.9	Ensembl	ENSP00000295956.5	46	MANE Select
NM_001164317.2	RefSeq	NP_001157789.1	47	Standard
NM_001164318.2	RefSeq	NP_001157790.1	46	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Focal adhesion - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Proteoglycans in cancer - Homo sapiens (human)
Focal Adhesion

Biological Process

keratinocyte development
epithelial cell morphogenesis
cytoskeletal anchoring at plasma membrane
signal transduction
skeletal muscle tissue development

Molecular Function

RNA binding
actin binding
protein binding
identical protein binding
cadherin binding

Cellular Component

stress fiber
cytoplasm
cytosol
plasma membrane
brush border

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000490882
Coding exons: 47
Length: 163856
Individuals with no LoFs: 125628
Homozygous LoFs: 0
Heterozygous LoFs: 120
Defined: 125748
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	1326	1.56e+3	0.848	0.0000973	17224
Missense (PolyPhen)		553	773.42	0.71501		8482
Synonymous	-0.129	666	662	1.01	0.0000486	5349
Loss of Function	6.50	38	112	0.338	0.00000586	1356

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0011	0.0011	notable
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00050	0.00049	rare
South Asian	0.00052	0.00052	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Connects cell membrane constituents to the actin cytoskeleton. May promote orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Various interactions and localizations of isoforms affect myotube morphology and myogenesis. Isoform 6 accelerates muscle differentiation in vitro.;
Disease: DISEASE: Note=Interaction with FLNA may compensate for dysfunctional FLNA homodimer in the periventricular nodular heterotopia (PVNH) disorder.; DISEASE: Atelosteogenesis 1 (AO1) [MIM:108720]: A lethal chondrodysplasia characterized by distal hypoplasia of the humeri and femurs, hypoplasia of the mid-thoracic spine, occasionally complete lack of ossification of single hand bones, and the finding in cartilage of multiple degenerated chondrocytes which are encapsulated in fibrous tissue. {ECO:0000269|PubMed:14991055}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atelosteogenesis 3 (AO3) [MIM:108721]: A short-limb lethal skeletal dysplasia with vertebral abnormalities, disharmonious skeletal maturation, poorly modeled long bones and joint dislocations. Recurrent respiratory insufficiency and/or infections usually result in early death. {ECO:0000269|PubMed:14991055}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Boomerang dysplasia (BOOMD) [MIM:112310]: A perinatal lethal osteochondrodysplasia characterized by absence or underossification of the limb bones and vertebrae. Patients manifest dwarfism with short, bowed, rigid limbs and characteristic facies. Boomerang dysplasia is distinguished from atelosteogenesis on the basis of a more severe defect in mineralization, with complete absence of ossification in some limb elements and vertebral segments. {ECO:0000269|PubMed:15994868}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Larsen syndrome (LRS) [MIM:150250]: An osteochondrodysplasia characterized by large-joint dislocations and characteristic craniofacial abnormalities. The cardinal features of the condition are dislocations of the hip, knee and elbow joints, with equinovarus or equinovalgus foot deformities. Spatula-shaped fingers, most marked in the thumb, are also present. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge, and a flattened midface. Cleft palate and short stature are often associated features. Spinal anomalies include scoliosis and cervical kyphosis. Hearing loss is a well-recognized complication. {ECO:0000269|PubMed:14991055, ECO:0000269|PubMed:16801345}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondylocarpotarsal synostosis syndrome (SCT) [MIM:272460]: Disorder characterized by short stature and vertebral, carpal and tarsal fusions. {ECO:0000269|PubMed:14991055}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.216

Intolerance Scores

LoFtool: 0.00269
RVIS EVS: -1.44
RVIS percentile EVS: 3.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.917

Gene Damage Prediction

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