FLG

filaggrin, the group of S100 fused type protein family|EF-hand domain containing

Basic information

Region (hg38): 1:152302165-152325239

Links

ENSG00000143631 ∙ NCBI:2312 ∙ OMIM:135940 ∙ HGNC:3748 ∙ Uniprot:P20930 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant ichthyosis vulgaris (Limited), mode of inheritance: AR
• autosomal dominant ichthyosis vulgaris (Strong), mode of inheritance: AD
• autosomal dominant ichthyosis vulgaris (Strong), mode of inheritance: AD
• autosomal dominant ichthyosis vulgaris (Definitive), mode of inheritance: Semidominant
• recessive X-linked ichthyosis (Supportive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Icthyosis vulgaris	AD/AR	General	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	Dermatologic	12473059; 12838398; 17030239; 16550169; 16444271; 16815158; 17291859; 21692775; 21712002; 21790526; 22299762; 22951058; 22962861; 22989708

ClinVar

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

• Inborn_genetic_diseases (1277 variants)
• not_provided (579 variants)
• Ichthyosis_vulgaris (170 variants)
• Dermatitis,_atopic,_2 (56 variants)
• FLG-related_disorder (43 variants)
• not_specified (33 variants)
• Autosomal_dominant_ichthyosis_vulgaris (11 variants)
• Dermatitis,_atopic,_2,_susceptibility_to (4 variants)
• Incidental_Discovery (2 variants)
• Eczematoid_dermatitis (2 variants)
• Ichthyosis (2 variants)
• Autosomal_recessive_congenital_ichthyosis (2 variants)
• Palmoplantar_keratodermas (1 variants)
• Paroxysmal_dystonia (1 variants)
• Atopic_eczema (1 variants)
• Palmoplantar_hyperhidrosis (1 variants)
• Microcephaly (1 variants)
• Feeding_difficulties (1 variants)
• Atrophic_scars (1 variants)
• Palmoplantar_blistering (1 variants)
• Abnormality_of_the_skin (1 variants)
• Dermatitis,_atopic (1 variants)
• See_cases (1 variants)
• Dry_skin (1 variants)
• Congenital_cerebellar_hypoplasia (1 variants)
• Ichthyosis_and_erythrokeratoderma (1 variants)
• Abnormality_of_salivation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLG gene is commonly pathogenic or not. These statistics are base on transcript: NM_000002016.2. 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	149	10	162
missense	1	1	1153	289	46	1490
nonsense	97	51	5			153
start loss						0
frameshift	54	41	4	2		101
splice donor/acceptor (+/-2bp)		2				2
Total	152	95	1165	440	56

Highest pathogenic variant AF is 0.0189727

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLG	protein_coding	protein_coding	ENST00000368799	2	23029

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000288	0.203	125623	0	11	125634	0.0000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-18.5	4436	2.07e+3	2.15	0.000126	25424
Missense in Polyphen		819	381.32	2.1478		4505
Synonymous	-21.0	1569	809	1.94	0.0000497	8052
Loss of Function	-1.69	4	1.65	2.42	6.88e-8	23

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000905	0.0000905
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000705	0.0000704
Middle Eastern	0.00	0.00
South Asian	0.0000329	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.
• Disease: DISEASE: Ichthyosis vulgaris (VI) [MIM:146700]: The most common form of ichthyosis inherited as an autosomal dominant trait. It is characterized by palmar hyperlinearity, keratosis pilaris and a fine scale that is most prominent over the lower abdomen, arms, and legs. Ichthyosis vulgaris is characterized histologically by absent or reduced keratohyalin granules in the epidermis and mild hyperkeratosis. The disease can be associated with frequent asthma, eczema or hay fever. {ECO:0000269|PubMed:16444271}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dermatitis atopic 2 (ATOD2) [MIM:605803]: Atopic dermatitis is a complex, inflammatory disease with multiple alleles at several loci thought to be involved in the pathogenesis. It commonly begins in infancy or early childhood and is characterized by a chronic relapsing form of skin inflammation, a disturbance of epidermal barrier function that culminates in dry skin, and IgE-mediated sensitization to food and environmental allergens. It is manifested by lichenification, excoriation, and crusting, mainly on the flexural surfaces of the elbow and knee. {ECO:0000269|PubMed:16550169, ECO:0000269|PubMed:16815158, ECO:0000269|PubMed:17030239, ECO:0000269|PubMed:17291859}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Keratinization;Developmental Biology;Formation of the cornified envelope (Consensus)

Intolerance Scores

• loftool: 0.995
• rvis_EVS: 24.3
• rvis_percentile_EVS: 99.99

Haploinsufficiency Scores

• pHI: 0.0897
• ghis: 0.389

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.284

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Gene ontology

• Biological process: multicellular organism development;peptide cross-linking;keratinocyte differentiation;establishment of skin barrier;cornification
• Cellular component: cornified envelope;nucleus;cytosol;intermediate filament;keratohyalin granule;intracellular membrane-bounded organelle;collagen-containing extracellular matrix
• Molecular function: structural molecule activity;calcium ion binding;protein binding;structural constituent of epidermis;transition metal ion binding