NIPBL
protein-codingNIPBL cohesin loading factor, the group of Armadillo like helical domain containing
Gene summary
This gene encodes the homolog of the Drosophila melanogaster Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins. The Drosophila protein facilitates enhancer-promoter communication of remote enhancers and plays a role in developmental regulation. It is also homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. The human protein has a bipartite nuclear targeting sequence and a putative HEAT repeat. Condensins, cohesins and other complexes with chromosome-related functions also contain HEAT repeats. Mutations in this gene result in Cornelia de Lange syndrome, a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and cognitive disability. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~189.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007387
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016033
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007387
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007387
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016033
Submitter: ClinGen
*NIPBL* was first reported in relation to autosomal dominant Cornelia de Lange syndrome (CdLS) in 2004 (Tonkin et al., PMID: 15146185; Krantz et al., PMID: 15146186). Thirteen variants (frameshift, nonsense, splice site, and missense) that have been reported in 13 probands in 2 publications (PMIDs: 15146185, 15146186) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants in this gene generally occur *de novo*. The mechanism of pathogenicity is known to be loss of function. A total of 243 unique variants have been classified as pathogenic in ClinVar, 193 of which are frameshift, nonsense or consensus splice changes. Classical CdLS features can be prenatally identified by fetal imaging; these include fetal growth restriction, limb reduction defects, hand anomalies including clinodactyly, oligodactyly, or ectrodactyly, diaphragmatic hernia, heart defects, microcephaly, and abnormal facial features including micrognathia, depressed nasal bridge, anteverted nares, long and smooth philtrum, thin upper lip and downturned corners of the mouth. Unusually long hair, synophrys with arched eyebrows and long eyelashes have been observed by two dimensional and three-dimensional ultrasound. CdLS can be prenatally suspected with any combination of fetal growth restriction, limb defects, facial abnormalities, heart defects, or diaphragmatic hernia (PMIDs: 19242925, 24218399, 24918291, 29995837, 30890023, 33478103, 33633789, 34394191, 35506482). Congenital heart disease is reported in about 30% of patients with CdLS, with pulmonic/peripheral pulmonic stenosis, ventricular septal defect and atrial septal defect being the most commonly found (PMID: 22965847). This gene-disease relationship is also supported by expression, protein interactions and animal models that recapitulate the human disease. In summary, there is definitive evidence supporting the relationship between *NIPBL* and autosomal dominant Cornelia de Lange syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This relationship was evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on June 20, 2018 (SOP 5), the Prenatal Gene Curation Expert Panel on June 28, 2023 (SOP 9), and the Congenital Heart Disease Gene Curation Expert Panel on August 11, 2025 (SOP 11).
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Renal
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
Comments: Somatic mosaicism is relatively frequent
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NIPBL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_133433.4. 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 | 4 | 35 | 319 | 12 | 371 |
| missense | 31 | 88 | 803 | 145 | 4 | 1071 |
| nonsense | 116 | 17 | 3 | 136 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 215 | 32 | 3 | 250 | ||
| splice donor/acceptor (+/-2bp) | 46 | 23 | 13 | 3 | 85 | |
| Total | 410 | 165 | 857 | 467 | 16 | 1915 |
Highest pathogenic variant AF is 0.0000020524974
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_597677.2 | 46 | MANE Select | |
| Ensembl | ENSP00000282516.8 | 46 | MANE Select | |
| RefSeq | NP_001425515.1 | 46 | Standard | |
| RefSeq | NP_056199.2 | 45 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nipbla | Danio rerio | Structure: post-vent region Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cohesin Loading onto Chromatin
- Mitotic Telophase/Cytokinesis
- M Phase
- Cell Cycle
- Cell Cycle, Mitotic
Biological Process
- negative regulation of transcription by RNA polymerase II
- metanephros development
- heart morphogenesis
- outflow tract morphogenesis
- double-strand break repair
Molecular Function
- chromatin binding
- protein binding
- protein C-terminus binding
- mediator complex binding
- histone deacetylase binding
Cellular Component
- nuclear chromosome
- chromatin
- nuclear chromatin
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000282516
- Coding exons
- 46
- Length
- 189655
- Individuals with no LoFs
- 125693
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125696
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.57 | 846 | 1.44e+3 | 0.587 | 0.0000738 | 18540 |
| Missense (PolyPhen) | 158 | 543.1 | 0.29092 | 7135 | ||
| Synonymous | -0.0351 | 496 | 495 | 1.00 | 0.0000249 | 5211 |
| Loss of Function | 11.3 | 1 | 150 | 0.00665 | 0.00000942 | 1781 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with MAU2/SCC4 which mediates the loading of the cohesin complex onto chromatin (PubMed:22628566, PubMed:28914604). Plays a role in cohesin loading at sites of DNA damage. Its recruitement to double-strand breaks (DSBs) sites occurs in a CBX3-, RNF8- and RNF168-dependent manner whereas its recruitement to UV irradiation-induced DNA damage sites occurs in a ATM-, ATR-, RNF8- and RNF168-dependent manner (PubMed:28167679). Along with ZNF609, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others (By similarity). {ECO:0000250|UniProtKB:Q6KCD5, ECO:0000269|PubMed:22628566, ECO:0000269|PubMed:28167679, ECO:0000269|PubMed:28914604}.;
- Disease
- DISEASE: Cornelia de Lange syndrome 1 (CDLS1) [MIM:122470]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. Characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:15146185, ECO:0000269|PubMed:15146186, ECO:0000269|PubMed:15318302, ECO:0000269|PubMed:20124326, ECO:0000269|PubMed:20358602, ECO:0000269|PubMed:21934712, ECO:0000269|PubMed:23254390, ECO:0000269|PubMed:25447906, ECO:0000269|PubMed:28167679}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.105
Intolerance Scores
- LoFtool
- 0.0000689
- RVIS EVS
- -2.45
- RVIS percentile EVS
- 1.01
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.992
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |