FERMT1
protein-codingFERM domain containing kindlin 1, the group of Fermitins|Pleckstrin homology domain containing|FERM domain containing
Gene summary
This gene encodes a member of the fermitin family, and contains a FERM domain and a pleckstrin homology domain. The encoded protein is involved in integrin signaling and linkage of the actin cytoskeleton to the extracellular matrix. Mutations in this gene have been linked to Kindler syndrome. [provided by RefSeq, Dec 2009]
- C20orf42
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~48.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: ClinGen
*FERMT1* was first reported in relation to autosomal recessive Kindler syndrome in 2003 (Siegel et al., PMID:12789646). However, Kindler syndrome was first described by Kindler T (PMID: 13149722) in 1954. Kindler syndrome is an autosomal recessive skin disorder characterized by blistering, photosensitivity, progressive poikiloderma, and extensive atrophy. Additional clinical features can include gingival erosions, ocular, esophageal, gastrointestinal and urogenital involvement, and milder disease phenotypes later onset. Thirteen variants (missense, nonsense, and frameshift) that have been reported in twelve probands in six publication (PMIDs: 12668616, 21936020, 24635080, 32973952, 17178989, 27862150) are included in this curation. Less than 150 cases of Kindler syndrome have been reported world wide, many within consanguineous families. More evidence is available in the literature, but many of the compound heterozygote probands do not meet the genetic testing guidelines of the ClinGen Genetic Evidence scoring matrix, therefore they do not contribute to the overall score. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models and expression studies (PMIDs: 12789646, 19057668, 30248333). Mice with disrupted Fermt1 gene, leading to complete loss of Kindlin-1 mRNA and protein (Kindlin-1-/-) have been shown to develop skin atrophy, thin epidermis, and postnatal lethality with complete penetrance. Also, experimental evidence indicating that *KIND1* (an alias form of *FERMT1*) is highly expressed in keratinocytes. *FERMT1* is directly involved with the biochemical process of keratinocyte migration via its connection to *EGFR*. When keratinocyte migration is impaired, it can cause impaired skin barriers (including dry, irritated skin (xerosis) and chronic, inflammatory rashes); while keratinocytes that fail to multiply properly can cause thinning of the epidermis (atrophy). In summary, there is definitive evidence supporting the relationship between *FERMT1* and autosomal recessive Kindler syndrome. 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 PIRD GCEP on April 8th, 2026 (SOP Version 12).
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008260
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Oncologic
Intervention: Dermatologic; Oncologic
Rationale: Individuals have an increased risk of squamous cell carcinoma and surveillance for premalignant keratoses/early malignancy may allow early diagnosis and treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FERMT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017671.5. 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 | 7 | 107 | 4 | 118 | ||
| missense | 1 | 175 | 9 | 5 | 190 | |
| nonsense | 14 | 3 | 3 | 20 | ||
| start loss | 0 | |||||
| frameshift | 13 | 5 | 3 | 21 | ||
| splice donor/acceptor (+/-2bp) | 8 | 10 | 6 | 24 | ||
| Total | 36 | 18 | 194 | 116 | 9 | 373 |
Highest pathogenic variant AF is 0.00012453717
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060141.3 | 14 | MANE Select | |
| Ensembl | ENSP00000217289.4 | 14 | MANE Select | |
| Ensembl | ENSP00000441063.2 | 2 | Standard | |
| Ensembl | ENSP00000514127.1 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fermt1 | Danio rerio | Structure: median fin Quality: ruffled abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- positive regulation of cell-matrix adhesion
- cell adhesion
- integrin-mediated signaling pathway
- negative regulation of gene expression
- positive regulation of transforming growth factor beta receptor signaling pathway
Molecular Function
- actin filament binding
Cellular Component
- cytosol
- cytoskeleton
- focal adhesion
- cell junction
- ruffle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000217289
- Coding exons
- 14
- Length
- 48700
- Individuals with no LoFs
- 125667
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 81
- Defined
- 125748
- p
- 0.000322
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.780 | 322 | 364 | 0.885 | 0.0000205 | 4474 |
| Missense (PolyPhen) | 101 | 130.73 | 0.77259 | 1683 | ||
| Synonymous | 0.507 | 133 | 141 | 0.946 | 0.00000870 | 1238 |
| Loss of Function | 2.28 | 23 | 38.2 | 0.602 | 0.00000192 | 444 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00055 | 0.00055 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.00035 | 0.00033 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in cell adhesion. Contributes to integrin activation. When coexpressed with talin, potentiates activation of ITGA2B. Required for normal keratinocyte proliferation. Required for normal polarization of basal keratinocytes in skin, and for normal cell shape. Required for normal adhesion of keratinocytes to fibronectin and laminin, and for normal keratinocyte migration to wound sites. May mediate TGF-beta 1 signaling in tumor progression. {ECO:0000269|PubMed:14634021, ECO:0000269|PubMed:17012746, ECO:0000269|PubMed:19804783}.;
- Disease
- DISEASE: Kindler syndrome (KNDLRS) [MIM:173650]: An autosomal recessive skin disorder characterized by skin blistering, photosensitivity, progressive poikiloderma, and extensive skin atrophy. Additional clinical features include gingival erosions, ocular, esophageal, gastrointestinal and urogenital involvement, and an increased risk of mucocutaneous malignancy. {ECO:0000269|PubMed:12668616, ECO:0000269|PubMed:12789646, ECO:0000269|PubMed:21936020}. Note=The disease is caused by mutations affecting the gene represented in this entry. Although most FERMT1 mutations are predicted to lead to premature termination of translation, and to loss of FERMT1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications (PubMed:21936020). {ECO:0000269|PubMed:21936020}.;
Recessive Scores
- pRec
- 0.145
Intolerance Scores
- LoFtool
- 0.471
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.79
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.217
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |