FLNA

filamin A, the group of Filamins

Basic information

Region (hg38): X:154348524-154374634

Previous symbols: [ "FLN1", "FLN", "OPD2", "OPD1" ]

Links

ENSG00000196924 ∙ ∙ OMIM:300017 ∙ HGNC:3754 ∙ Uniprot:P21333 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• heterotopia, periventricular, X-linked dominant (Definitive), mode of inheritance: XL
• otopalatodigital syndrome type 2 (Moderate), mode of inheritance: XL
• cardiac valvular dysplasia, X-linked (Moderate), mode of inheritance: XL
• heterotopia, periventricular, X-linked dominant (Definitive), mode of inheritance: XL
• congenital short bowel syndrome (Supportive), mode of inheritance: AR
• frontometaphyseal dysplasia (Supportive), mode of inheritance: AD
• Melnick-Needles syndrome (Supportive), mode of inheritance: XL
• X-linked Ehlers-Danlos syndrome (Supportive), mode of inheritance: XL
• terminal osseous dysplasia-pigmentary defects syndrome (Supportive), mode of inheritance: XL
• otopalatodigital syndrome type 1 (Supportive), mode of inheritance: XL
• otopalatodigital syndrome type 2 (Supportive), mode of inheritance: XL
• periventricular nodular heterotopia (Supportive), mode of inheritance: AD
• cardiac valvular dysplasia, X-linked (Supportive), mode of inheritance: XL
• terminal osseous dysplasia-pigmentary defects syndrome (Definitive), mode of inheritance: XL
• Melnick-Needles syndrome (Definitive), mode of inheritance: XL
• otopalatodigital syndrome type 2 (Definitive), mode of inheritance: XL
• heterotopia, periventricular, X-linked dominant (Definitive), mode of inheritance: XL
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked (Definitive), mode of inheritance: XL
• frontometaphyseal dysplasia 1 (Definitive), mode of inheritance: XL
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked (Strong), mode of inheritance: XL
• Melnick-Needles syndrome (Strong), mode of inheritance: XL
• cardiac valvular dysplasia, X-linked (Strong), mode of inheritance: XL
• otopalatodigital syndrome type 2 (Strong), mode of inheritance: XL
• heterotopia, periventricular, X-linked dominant (Strong), mode of inheritance: XL
• terminal osseous dysplasia-pigmentary defects syndrome (Strong), mode of inheritance: XL
• familial thoracic aortic aneurysm and aortic dissection (Limited), mode of inheritance: XL
• periventricular nodular heterotopia (Definitive), mode of inheritance: XL
• genetic developmental and epileptic encephalopathy (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiac valvular dysplasia, X-linked; Heterotopia, periventricular, 1; Intestinal pseudoobstruction, neuronal, X-linked/Congenital short bowel syndrome	XL	Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal	In Cardiac valvular dysplasia, X-linked, surveillance for and correction of valvular anomalies can be beneficial; Individuals with Heterotopia, periventricular may have cardiac and vascular anomalies, which may warrant surveillance and medical/surgical management; For hearing loss, early recognition may allow beneficial interventions that can help with speech and language development; In Intestinal pseudoobstruction, neuronal, X-linked/Congenital short bowel syndrome, individuals have been described as benefiting from early introduction of enteral feeds, with later weaning from parenteral nutrition, and awareness of the risk of other GI-related complications may allow prompt recognition and management	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Pulmonary; Renal	5938049; 5807657; 8230166; 8290091; 8644737; 9883725; 9800904; 9497244; 10982965; 11857561; 11914408; 12612583; 15249610; 14988809; 15864382; 15940695; 15654694; 15523633; 15917206; 15654694; 15668422; 16299064; 16538226; 16596676; 16926860; 17152064; 17190868; 17264970; 17357080; 17431908; 17632775; 18209785; 18427995; 18854860; 19917821; 20301567; 20014127; 20598277; 20730588; 20888935; 21031081; 21194575; 21412975; 21484998; 21815255; 21960593; 22238415; 22366253; 22740120; 23037936; 23873601

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FLNA gene.

• Heterotopia,_periventricular,_X-linked_dominant (2929 variants)
• Melnick-Needles_syndrome (2871 variants)
• Oto-palato-digital_syndrome,_type_II (2868 variants)
• Frontometaphyseal_dysplasia (2850 variants)
• not_provided (1163 variants)
• Familial_thoracic_aortic_aneurysm_and_aortic_dissection (990 variants)
• not_specified (403 variants)
• FLNA-related_disorder (252 variants)
• Cardiac_valvular_dysplasia,_X-linked (97 variants)
• FG_syndrome_2 (81 variants)
• Oto-palato-digital_syndrome,_type_I (77 variants)
• Frontometaphyseal_dysplasia_1 (75 variants)
• Intestinal_pseudoobstruction,_neuronal,_chronic_idiopathic,_X-linked (67 variants)
• Terminal_osseous_dysplasia-pigmentary_defects_syndrome (64 variants)
• Connective_tissue_disorder (41 variants)
• Intellectual_disability (10 variants)
• See_cases (8 variants)
• Thrombocytopenia (7 variants)
• Inborn_genetic_diseases (5 variants)
• Periventricular_nodular_heterotopia (5 variants)
• Macrothrombocytopenia (5 variants)
• Cardiovascular_phenotype (4 variants)
• Ehlers-Danlos_syndrome (3 variants)
• Prune_belly_syndrome (3 variants)
• FLNA_related_lung_disease (2 variants)
• Microcephaly (2 variants)
• Seizure (2 variants)
• Neurodevelopmental_delay (2 variants)
• Patent_ductus_arteriosus (2 variants)
• Otopalatodigital_syndrome_spectrum_disorder (2 variants)
• Attenuated_frontometaphyseal_dysplasia (2 variants)
• Incidental_Discovery (1 variants)
• Congenital_heart_disease (1 variants)
• Abnormal_bleeding (1 variants)
• Ventricular_septal_defect (1 variants)
• Abnormality_of_the_dentition (1 variants)
• HETEROTOPIA,_PERIVENTRICULAR_NODULAR,_X-LINKED_DOMINANT,_WITH_MELNICK-NEEDLES_SYNDROME (1 variants)
• Ambiguous_genitalia (1 variants)
• Dysplastic_corpus_callosum (1 variants)
• Aortic_dilatation (1 variants)
• FLNA-related_otopalatodigital_spectrum_disorders (1 variants)
• Scoliosis (1 variants)
• HETEROTOPIA,_PERIVENTRICULAR_NODULAR,_X-LINKED,_WITH_FRONTOMETAPHYSEAL_DYSPLASIA (1 variants)
• Laterality_defects,_autosomal_dominant (1 variants)
• Thoracic_aortic_aneurysm_or_dissection (1 variants)
• Sudden_unexplained_death_in_childhood (1 variants)
• Patent_foramen_ovale (1 variants)
• Aortic_aneurysm,_familial_thoracic_2 (1 variants)
• Neurodevelopmental_disorder (1 variants)
• History_of_neurodevelopmental_disorder (1 variants)
• Arterial_thrombosis (1 variants)
• Hearing_impairment (1 variants)
• Otopalatodigital_Spectrum_Disorders (1 variants)
• Intellectual_disability,_severe (1 variants)
• Marfan_syndrome (1 variants)
• Short_stature (1 variants)
• Hereditary_breast_ovarian_cancer_syndrome (1 variants)
• Vascular_dilatation (1 variants)
• CONGENITAL_SHORT_BOWEL_SYNDROME,_X-LINKED (1 variants)
• Ventral_hernia (1 variants)
• Heart,_malformation_of (1 variants)
• Disorder_of_sexual_differentiation (1 variants)
• Myopia (1 variants)
• Abnormal_cerebral_morphology (1 variants)
• Myopathy,_centronuclear,_2 (1 variants)
• Abnormality_of_the_face (1 variants)
• Arterial_tortuosity (1 variants)
• Conductive_hearing_impairment (1 variants)
• Hypotonia (1 variants)
• Abnormality_of_neuronal_migration (1 variants)
• Hepatoblastoma (1 variants)
• Wolff-Parkinson-White_pattern (1 variants)
• Orofacial_cleft (1 variants)
• FLNA-related_periventricular_nodular_heterotopia (1 variants)
• Global_developmental_delay (1 variants)
• Ehlers-Danlos_syndrome,_classic_type (1 variants)
• Developmental_delay (1 variants)
• Hydronephrosis (1 variants)
• Congenital_omphalocele (1 variants)
• Cleft_palate (1 variants)
• Flexion_contracture (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLNA gene is commonly pathogenic or not. These statistics are base on transcript: NM_001110556.2. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	3	2	30	983	51	1069
missense	21	37	1163	453	83	1757
nonsense	47	20	1			68
start loss		1				1
frameshift	106	34	3			143
splice donor/acceptor (+/-2bp)	20	32	2			54
Total	197	126	1199	1436	134

Highest pathogenic variant AF is 0.000009011851

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLNA	protein_coding	protein_coding	ENST00000369850	47	26115

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.81e-11	124778	1	4	124783	0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.78	867	1.24e+3	0.698	0.000113	17220
Missense in Polyphen		219	444.5	0.49269		6188
Synonymous	-2.98	665	574	1.16	0.0000604	5512
Loss of Function	7.89	2	76.5	0.0261	0.00000533	1304

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000365	0.0000365
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000496	0.0000353
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface- localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q8BTM8, ECO:0000269|PubMed:22121117}.
• Disease: DISEASE: Periventricular nodular heterotopia 1 (PVNH1) [MIM:300049]: A developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH1 is an X-linked dominant form. Heterozygous females have normal intelligence but suffer from seizures and various manifestations outside the central nervous system, especially related to the vascular system. Hemizygous affected males die in the prenatal or perinatal period. {ECO:0000269|PubMed:11532987, ECO:0000269|PubMed:11914408, ECO:0000269|PubMed:15249610, ECO:0000269|PubMed:15668422, ECO:0000269|PubMed:15994863, ECO:0000269|PubMed:16299064}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Otopalatodigital syndrome 1 (OPD1) [MIM:311300]: X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. FLNA is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. Males with OPD1 have cleft palate, malformations of the ossicles causing deafness and milder bone and limb defects than those associated with OPD2. Obligate female carriers of mutations causing both OPD1 and OPD2 have variable (often milder) expression of a similar phenotypic spectrum. {ECO:0000269|PubMed:12612583, ECO:0000269|PubMed:15940695, ECO:0000269|PubMed:27193221}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Otopalatodigital syndrome 2 (OPD2) [MIM:304120]: Congenital bone disorder that is characterized by abnormally modeled, bowed bones, small or absent first digits and, more variably, cleft palate, posterior fossa brain anomalies, omphalocele and cardiac defects. {ECO:0000269|PubMed:12612583, ECO:0000269|PubMed:17431908, ECO:0000269|PubMed:27193221}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Frontometaphyseal dysplasia 1 (FMD1) [MIM:305620]: An X- linked disease characterized by generalized skeletal dysplasia, deafness, and urogenital defects. {ECO:0000269|PubMed:12612583, ECO:0000269|PubMed:16596676, ECO:0000269|PubMed:27193221}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Melnick-Needles syndrome (MNS) [MIM:309350]: Severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull. {ECO:0000269|PubMed:12612583, ECO:0000269|PubMed:27193221}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked (IPOX) [MIM:300048]: A disease characterized by a severe abnormality of gastrointestinal motility due to primary qualitative defects of enteric ganglia and nerve fibers. Affected individuals manifest recurrent signs of intestinal obstruction in the absence of any mechanical lesion. {ECO:0000269|PubMed:17357080}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: FG syndrome 2 (FGS2) [MIM:300321]: FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. {ECO:0000269|PubMed:17632775}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Terminal osseous dysplasia (TOD) [MIM:300244]: A rare X- linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma during infancy. A significant phenotypic variability is observed in affected females. {ECO:0000269|PubMed:20598277}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiac valvular dysplasia X-linked (CVDX) [MIM:314400]: A rare X-linked heart disease characterized by mitral and/or aortic valve regurgitation. The histologic features include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans, which produces excessive valve tissue leading to billowing of the valve leaflets. {ECO:0000269|PubMed:17190868}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abnormally enlarged (PubMed:21960593). {ECO:0000269|PubMed:21960593}.; DISEASE: Congenital short bowel syndrome, X-linked (CSBSX) [MIM:300048]: A disease characterized by a shortened small intestine, and malabsorption. The mean length of the small intestine in affected individuals is approximately 50 cm, compared with a normal length at birth of 190-280 cm. It is associated with significant mortality and morbidity. Infants usually present with failure to thrive, recurrent vomiting, and diarrhea. {ECO:0000269|PubMed:23037936}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Focal adhesion - Homo sapiens (human);Salmonella infection - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);EGF-Ncore;Androgen receptor signaling pathway;Prolactin Signaling Pathway;JAK-STAT;Focal Adhesion;Hypothesized Pathways in Pathogenesis of Cardiovascular Disease;MAPK Signaling Pathway;IL-4 Signaling Pathway;Signal Transduction;Prolactin;GP1b-IX-V activation signalling;AndrogenReceptor;RHO GTPases activate PAKs;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;RHO GTPase Effectors;Signaling by Rho GTPases;Hemostasis;Noncanonical Wnt signaling pathway;TNFalpha;Cell-extracellular matrix interactions;Cell junction organization;Cell-Cell communication;TCR signaling in naïve CD4+ T cells (Consensus)

Recessive Scores

• pRec: 0.644

Intolerance Scores

• loftool: 0.000896
• rvis_EVS: -3.24
• rvis_percentile_EVS: 0.44

Haploinsufficiency Scores

• pHI: 0.741
• hipred: Y
• hipred_score: 0.831
• ghis: 0.540

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.972

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Flna
• Phenotype: growth/size/body region phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; liver/biliary system phenotype; respiratory system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype

Gene ontology

• Biological process: platelet degranulation;adenylate cyclase-inhibiting dopamine receptor signaling pathway;negative regulation of transcription by RNA polymerase I;formation of radial glial scaffolds;cerebral cortex development;platelet activation;regulation of cell migration;actin cytoskeleton reorganization;positive regulation of actin filament bundle assembly;cell junction assembly;protein localization to cell surface;negative regulation of protein catabolic process;positive regulation of protein import into nucleus;mRNA transcription by RNA polymerase II;negative regulation of apoptotic process;receptor clustering;positive regulation of I-kappaB kinase/NF-kappaB signaling;negative regulation of DNA-binding transcription factor activity;wound healing, spreading of cells;establishment of protein localization;protein stabilization;cytoplasmic sequestering of protein;defense response to virus;actin crosslink formation;cilium assembly;platelet aggregation;semaphorin-plexin signaling pathway;protein localization to plasma membrane;mitotic spindle assembly;establishment of Sertoli cell barrier;positive regulation of substrate adhesion-dependent cell spreading;positive regulation of potassium ion transmembrane transport;protein localization to bicellular tight junction;regulation of membrane repolarization during atrial cardiac muscle cell action potential;regulation of membrane repolarization during cardiac muscle cell action potential;positive regulation of neural precursor cell proliferation;positive regulation of integrin-mediated signaling pathway;positive regulation of neuron migration
• Cellular component: extracellular region;nucleus;nucleolus;cytoplasm;cytosol;plasma membrane;cell-cell junction;focal adhesion;actin cytoskeleton;membrane;Z disc;cortical cytoskeleton;Myb complex;filamentous actin;neuronal cell body;dendritic shaft;perinuclear region of cytoplasm;extracellular exosome;apical dendrite;postsynapse;glutamatergic synapse
• Molecular function: G protein-coupled receptor binding;RNA binding;protein binding;transcription factor binding;potassium channel regulator activity;Rho GTPase binding;Ral GTPase binding;kinase binding;small GTPase binding;mu-type opioid receptor binding;Fc-gamma receptor I complex binding;protein homodimerization activity;ion channel binding;cadherin binding;SMAD binding;Rac GTPase binding;actin filament binding;GTPase binding