NPPA
protein-codingnatriuretic peptide A, the group of Neuropeptides
Gene summary
The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]
- ANP
- PND
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014329
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015281
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0005021
Submitter: ClinGen
Natriuretic Peptide Precursor A (NPPA) was originally evaluated for autosomal recessive dilated cardiomyopathy (DCM) on October 25th, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on September 6th 2024. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. NPPA encodes ANP (atrial natriuretic peptide) a cardiac hormone produced in the atria and released in pathological conditions (e.g. heart failure, hypertrophy) associated with increased atrial wall stress (Lekanne Deprez et al, 1998, PMID: 9769242). There is no supporting human genetic evidence demonstrating this gene-disease relationship in the literature at the time of curation. Variants in this gene have been found to be associated with autosomal dominant atrial fibrillation and autosomal recessive Atrial Dilated Cardiomyopathy with Standstill Evolution (OMIM 108780; Disertori et al, 2013, PMID: 23275345). The 13 patients with autosomal recessive Atrial Dilated Cardiomyopathy with Standstill Evolution were followed up to 37 years and showed normal left ventricular function and stable New York Heart Association functional class during the long-term course of the disease. No signs of a dilated (ventricular) cardiomyopathy. So far no disease association with DCM has been published. However, this gene-disease association is supported by expression studies. Using human iPS cell derived cardiomyocytes and mouse models to analyze transcription factors involved in DCM pathogenesis, NPPA was identified to have been expressed in heart tissue, and upregulated in heart tissue derived from DCM patients (Feng et. al, 2022, PMID: 35400201). Additionally, in a study to assess underlying genes that could be utilized as diagnostic biomarkers for DCM in heart failure patients, single-cell RNA-sequencing analysis of NPPA in DCM patient derived cardiomyocytes identified increased expression of NPPA (Zhu et. al, 2022, PMID: 36544902). Finally, a study assessing expression in left vertical myocardial tissues obtained from explanted hearts noted that NPPA is expressed in the heart and positively correlated with LVESD (Schiana et. al, 2021, PMID: 34946895). No convincing evidence for a casual role for NPPA and autosomal dominant DCM has been reported. Although this gene-disease assertion is supported by expression studies, no reports have directly implicated the gene in humans. This re-classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on September 6th, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0012816
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012816
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0012816
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Surveillance, preventive measures, and early medical intervention to prevent morbidity related to arrhthymias (atrial standstill/atrial fibrillation, depending on the inheritance pattern) may be beneficial
Comments: The clinical onset of manifestations has been described in the adult period, but earlier surveillance may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPPA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006172.4. 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 | 2 | 36 | 38 | |||
| missense | 87 | 8 | 95 | |||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 1 | 95 | 44 | 0 | 140 |
Highest pathogenic variant AF is 6.842772e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006163.1 | 3 | MANE Select | |
| Ensembl | ENSP00000365663.3 | 3 | MANE Select | |
| Ensembl | ENSP00000365659.1 | 2 | Standard | |
| Ensembl | ENSP00000623389.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HIF-1 signaling pathway - Homo sapiens (human)
- Physiological factors
- MicroRNAs in cardiomyocyte hypertrophy
- YAP1- and WWTR1 (TAZ)-stimulated gene expression
- Cardiac Hypertrophic Response
Biological Process
- response to hypoxia
- negative regulation of systemic arterial blood pressure
- cGMP biosynthetic process
- transcription initiation from RNA polymerase II promoter
- protein folding
Molecular Function
- signaling receptor binding
- hormone activity
- neuropeptide hormone activity
- protein binding
- hormone receptor binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- cytoplasm
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000376480
- Coding exons
- 3
- Length
- 2637
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125748
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.266 | 100 | 92.8 | 1.08 | 0.00000559 | 976 |
| Missense (PolyPhen) | 28 | 28.739 | 0.97429 | 297 | ||
| Synonymous | -0.630 | 45 | 39.9 | 1.13 | 0.00000256 | 320 |
| Loss of Function | 0.189 | 5 | 5.48 | 0.913 | 2.98e-7 | 59 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000063 | 0.000062 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000080 | 0.000079 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Hormone playing a key role in cardiovascular homeostasis through regulation of natriuresis, diuresis, and vasodilation. Also plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus. Specifically binds and stimulates the cGMP production of the NPR1 receptor. Binds the clearance receptor NPR3. {ECO:0000269|PubMed:1672777}.;
- Disease
- DISEASE: Atrial standstill 2 (ATRST2) [MIM:615745]: A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. {ECO:0000269|PubMed:23275345}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial fibrillation, familial, 6 (ATFB6) [MIM:612201]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:18614783}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.581
Intolerance Scores
- LoFtool
- 0.640
- RVIS EVS
- 0.86
- RVIS percentile EVS
- 88.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |