NACC1
protein-codingnucleus accumbens associated 1, the group of BTB domain containing|BEN domain containing
Gene summary
This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance. The encoded protein also suppresses transcription of the candidate tumor suppressor Gadd45GIP1, and expression of this gene may play a role in the progression of multiple types of cancer. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Feb 2012]
- BTBD14B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0044306
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0800475
Submitter: ClinGen
*NACC1* was first reported in relation to autosomal dominant *NACC1*-related neurodevelopmental disorder with epilepsy, cataracts, and episodic irritability in 2017 (Schoch et al., PMID: 28132692). Over 15 individuals with a recurrent *de novo* missense variant, c.892C>T, p.Arg298Trp, have been reported (PMIDs: 27479843, 28132692, 30842647, 31231135, 33057194, 34869110, 35719373, 37667351). They presented with severe to profound developmental delay or intellectual disability, epilepsy, feeding difficulties, and periodic extreme irritability and inconsolability (PMID: 37667351). Other frequent features include hypotonia, microcephaly, bilateral cataracts, brain MRI abnormalities, and sleep disorder. Only 12 probands are included in this curation because the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity of this variant is reported to be dominant negative (PMID: 37533751). Other *NACC1* missense (PMIDs: 31618753, 31785789, 33057194, 35982159, 36028527) or splice (PMID: 31981491) variants have also been reported in individuals with neurodevelopmental disorders, however, they were not scored in the current curation due to a lack of evidence supporting variant pathogenicity. This gene-disease relationship is also supported by the biochemical function of NACC1 as a transcriptional repressor (PMID: 16033423), protein interactions with key synaptic proteins involved in neurodevelopmental disorders (PMID: 37533751), and in vitro studies in mouse neurons expressing the murine homolog of the human mutant showing that the p.Arg298Trp variant impairs glutamatergic neurotransmission (PMID: 37533751). In summary, there is definitive evidence supporting the relationship between the *NACC1* recurrent variant p.Arg298Trp and *NACC1*-related neurodevelopmental disorder with epilepsy, cataracts, and episodic irritability. 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 October 4, 2023 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0044306
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0044306
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0044306
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic; Ophthalmologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NACC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_052876.4. 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 | 4 | 179 | 9 | 192 | ||
| missense | 3 | 7 | 189 | 30 | 30 | 259 |
| nonsense | 8 | 8 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 7 | 204 | 209 | 39 | 462 |
Highest pathogenic variant AF is 0.00000205227
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_443108.1 | 5 | MANE Select | |
| Ensembl | ENSP00000292431.3 | 5 | MANE Select | |
| Ensembl | ENSP00000466017.1 | 2 | Standard | |
| Ensembl | ENSP00000467120.2 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- positive regulation of cell population proliferation
- negative regulation of transcription, DNA-templated
- protein homooligomerization
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- nuclear body
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000292431
- Coding exons
- 5
- Length
- 23039
- Individuals with no LoFs
- 124497
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 124499
- p
- 0.00000803
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.17 | 143 | 368 | 0.389 | 0.0000256 | 3426 |
| Missense (PolyPhen) | 20 | 108.89 | 0.18367 | 1063 | ||
| Synonymous | 0.347 | 166 | 172 | 0.966 | 0.0000140 | 1062 |
| Loss of Function | 3.90 | 0 | 17.7 | 0.00 | 8.45e-7 | 189 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000010 | 0.0000089 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as a transcriptional repressor. Seems to function as a transcriptional corepressor in neuronal cells through recruitment of HDAC3 and HDAC4. Contributes to tumor progression, and tumor cell proliferation and survival. This may be mediated at least in part through repressing transcriptional activity of GADD45GIP1. Required for recruiting the proteasome from the nucleus to the cytoplasm and dendritic spines. {ECO:0000269|PubMed:17130457, ECO:0000269|PubMed:17804717}.;
Recessive Scores
- pRec
- 0.112
Intolerance Scores
- LoFtool
- 0.0304
- RVIS EVS
- -0.2
- RVIS percentile EVS
- 38.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.675
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |