NPHS1
protein-codingNPHS1 adhesion molecule, nephrin, the group of Fibronectin type III domain containing|V-set domain containing|C2-set domain containing
Gene summary
This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: ClinGen
The *NPHS1* gene is located on chromosome 19 at 19q13.12 and encodes the protein nephrin, which forms the slit diaphragm between podocyte foot processes (the glomerular filtration barrier in the kidney). *NPHS1* was first reported in relation to autosomal recessive nephrotic syndrome type 1 in 1994 (Kestila et al., PMID: 8178817). The preferred disease name suggested for this disorder is ‘Nephrotic syndrome - *NPHS1*’. The mechanism of pathogenicity is known to be loss of function. The disorder is characterized by significant protein loss in the urine within the first weeks of life causing generalized edema. At least 26 variants (frameshift, nonsense, splice, missense) have been reported in 71 probands in 4 publications (PMIDs: 8178817, 9660941, 9915943, 18503012 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by animal models, expression studies, in vitro functional assays, and rescue assays. In particular, nephrin knockout mice showed congenital nephrotic syndrome (PMID 11136707) which could be rescued using doxycycline-induced expression of rat nephrin (PMID 19948823), nephrin expression was demonstrated in normal kidneys but lost in patients with autosomal recessive frameshift or nonsense *NPHS1* mutations (PMID 10972661), and in-vitro functional assays demonstrated a nonsense *NPHS1* mutation stopped nephrin-mediated signalling of intracellular pathways AP-1 and MAPK (PMID 11562357), whilst certain missense *NPHS1* mutations caused nephrin accumulation in the endoplasmic reticulum, preventing its expression at the cell surface (PMID 11726550). A total of 5.5/6 pts. for experimental evidence was reached In summary, there is definitive evidence supporting the relationship between *NPHS1* autosomal recessive nephrotic syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0019006
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009732
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Renal
Intervention: General
Rationale: 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
Comments: Medical therapy to control bacterial infections, along with renal transplantation, can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPHS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004646.4. 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 | 1 | 20 | 607 | 5 | 633 | |
| missense | 12 | 92 | 408 | 96 | 3 | 611 |
| nonsense | 47 | 40 | 3 | 90 | ||
| start loss | 3 | 3 | ||||
| frameshift | 119 | 127 | 3 | 249 | ||
| splice donor/acceptor (+/-2bp) | 12 | 82 | 1 | 95 | ||
| Total | 190 | 345 | 435 | 703 | 8 | 1681 |
Highest pathogenic variant AF is 0.0004398987
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004637.1 | 29 | MANE Select | |
| Ensembl | ENSP00000368190.4 | 29 | MANE Select | |
| Ensembl | ENSP00000343634.5 | 28 | Standard | |
| Ensembl | ENSP00000343634.5 | 28 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nphs1 | Danio rerio | Structure: skeletal muscle cell Quality: mislocalised abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Primary Focal Segmental Glomerulosclerosis FSGS
- Nephrin family interactions
- Cell-Cell communication
- Nephrin/Neph1 signaling in the kidney podocyte
Biological Process
- cell adhesion
- JNK cascade
- skeletal muscle tissue development
- myoblast fusion
- excretion
Molecular Function
- protein binding
- myosin binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- slit diaphragm
- cell projection
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378910
- Coding exons
- 29
- Length
- 43324
- Individuals with no LoFs
- 125254
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 494
- Defined
- 125748
- p
- 0.00197
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.408 | 698 | 729 | 0.957 | 0.0000436 | 7848 |
| Missense (PolyPhen) | 198 | 224.96 | 0.88016 | 2563 | ||
| Synonymous | -1.04 | 346 | 322 | 1.07 | 0.0000209 | 2677 |
| Loss of Function | 3.53 | 33 | 63.4 | 0.521 | 0.00000335 | 677 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00057 | 0.00055 | rare |
| Latino/Admixed American | 0.00085 | 0.00084 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.012 | 0.012 | notable |
| European (Non-Finnish) | 0.0013 | 0.0013 | notable |
| South Asian | 0.0011 | 0.00098 | notable |
| Other | 0.0016 | 0.0016 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Seems to play a role in the development or function of the kidney glomerular filtration barrier. Regulates glomerular vascular permeability. May anchor the podocyte slit diaphragm to the actin cytoskeleton. Plays a role in skeletal muscle formation through regulation of myoblast fusion (By similarity). {ECO:0000250|UniProtKB:Q9QZS7, ECO:0000250|UniProtKB:Q9R044}.;
- Disease
- DISEASE: Nephrotic syndrome 1 (NPHS1) [MIM:256300]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. {ECO:0000269|PubMed:10652016, ECO:0000269|PubMed:11317351, ECO:0000269|PubMed:11726550, ECO:0000269|PubMed:17290294, ECO:0000269|PubMed:18503012, ECO:0000269|PubMed:18614772, ECO:0000269|PubMed:20172850, ECO:0000269|PubMed:20798252, ECO:0000269|PubMed:22009864, ECO:0000269|PubMed:22565185, ECO:0000269|PubMed:22732337, ECO:0000269|PubMed:25804400, ECO:0000269|PubMed:26560236, ECO:0000269|PubMed:9660941, ECO:0000269|PubMed:9915943}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.535
Intolerance Scores
- LoFtool
- 0.574
- RVIS EVS
- 0.68
- RVIS percentile EVS
- 84.95
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |