ADNP
protein-codingactivity dependent neuroprotector homeobox, the group of ZF class homeoboxes and pseudogenes
Gene summary
Vasoactive intestinal peptide is a neuroprotective factor that has a stimulatory effect on the growth of some tumor cells and an inhibitory effect on others. This gene encodes a protein that is upregulated by vasoactive intestinal peptide and may be involved in its stimulatory effect on certain tumor cells. The encoded protein contains one homeobox and nine zinc finger domains, suggesting that it functions as a transcription factor. This gene is also upregulated in normal proliferative tissues. Finally, the encoded protein may increase the viability of certain cell types through modulation of p53 activity. Alternatively spliced transcript variants encoding the same protein have been described. [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 ~42.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014379
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014379
Submitter: Illumina
The ADNP gene is located on chromosome 20 at 20q13.13 and encodes the activity dependent neuroprotector homeobox protein, which regulates gene expression via chromatin remodeling. ADNP was first reported in relation to autosomal dominant ADNP-related multiple congenital anomalies-intellectual disability-autism spectrum disorder in 2014 (24531329: Helsmoortel et al. 2014). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least five unique de novo loss-of-function variants have been reported in probands from three publications (24531329: Helsmoortel et al. 2014; 25057125: Pescosolido et al. 2014; 31029150: Bend et al. 2019). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by protein interaction with SWI/SNF chromatin remodelling complex subunits, dysregulated gene expression in ADNP knockout mouse embryos, and a heterozygous knockout mouse model that shows strong phenotypic overlap with human patients (17878164: Mandel & Gozes 2007; 17222401: Mandel et al. 2007; 30106381: Hacohen-Kleiman et al. 2018). In summary, ADNP is definitively associated with autosomal dominant ADNP-related multiple congenital anomalies-intellectual disability-autism spectrum disorder. 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:0014379
Submitter: ClinGen
*ADNP* was first reported in relation to autosomal dominant ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, also known as Helsmoortel-Van Der Aa syndrome, in 2014 (Helsmoortel et al., PMID: 24531329). The disorder is characterized by hypotonia, speech and motor delay, intellectual disability, autism or autistic features, and dysmorphic facial features. Other common findings include sleep disturbances, structural brain abnormalities, feeding issues, gastrointestinal abnormalities, visual defects, musculoskeletal anomalies, recurrent infections, cardiac abnormalities, and urinary tract abnormalities. Truncating variants in *ADNP* have been reported in at least 18 probands in four publications (PMIDs: 24531329, 25057125, 30107084, 31127536). Eight variants (nonsense, frameshift) that have been reported in 10 probands in two publications (PMIDs: 24531329, 25057125) are included in this curation. Variants were *de novo* in all instances in which parental DNA was available. All of the curated variants are located in the last exon and are predicted to escape nonsense-mediated mRNA decay. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function. ADNP is a homeodomain-containing zinc finger protein with transcription factor activity that is essential for brain formation. ADNP interacts with components of the BAF complex, a chromatin remodeling complex involved in the regulation of gene expression. This gene-disease relationship is also supported by a mouse model. In summary, there is definitive evidence supporting the relationship between *ADNP* and autosomal dominant ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on January 15, 2020 (SOP Version 7).
Inheritance Pattern: Unknown
Disease ID:MONDO:0014379
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014379
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014379
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ADNP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001282531.3. 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 | 18 | 157 | 16 | 191 | ||
| missense | 9 | 381 | 151 | 4 | 545 | |
| nonsense | 34 | 10 | 2 | 46 | ||
| start loss | 2 | 2 | ||||
| frameshift | 76 | 48 | 7 | 131 | ||
| splice donor/acceptor (+/-2bp) | 1 | 4 | 4 | 9 | ||
| Total | 113 | 71 | 412 | 308 | 20 | 924 |
Highest pathogenic variant AF is 0.00001983217
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001269460.1 | 3 | MANE Select | |
| Ensembl | ENSP00000483881.1 | 3 | MANE Select | |
| RefSeq | NP_001269461.1 | 3 | Standard | |
| RefSeq | NP_001334440.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| adnpa | Danio rerio | Structure: blood cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of transcription by RNA polymerase II
- short-term memory
- response to carbohydrate
- response to inorganic substance
- negative regulation of gene expression
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- chromatin binding
- copper ion binding
- protein binding
Cellular Component
- extracellular space
- nucleus
- cytoplasm
- axon
- dendrite
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396029
- Coding exons
- 3
- Length
- 42374
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125739
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.07 | 439 | 579 | 0.758 | 0.0000300 | 7343 |
| Missense (PolyPhen) | 57 | 189.87 | 0.3002 | 2552 | ||
| Synonymous | -3.92 | 288 | 215 | 1.34 | 0.0000118 | 2066 |
| Loss of Function | 5.61 | 1 | 38.7 | 0.0259 | 0.00000227 | 486 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Potential transcription factor. May mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation.;
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- LoFtool
- 0.00689
- RVIS EVS
- -1.41
- RVIS percentile EVS
- 4.13
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.881
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |