NPPA

natriuretic peptide A, the group of Neuropeptides

Basic information

Region (hg38): 1:11845708-11848345

Previous symbols: [ "ANP", "PND" ]

Links

ENSG00000175206 ∙ NCBI:4878 ∙ OMIM:108780 ∙ HGNC:7939 ∙ Uniprot:P01160 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• atrial fibrillation, familial, 6 (Moderate), mode of inheritance: AD
• atrial standstill (Supportive), mode of inheritance: AD
• familial atrial fibrillation (Supportive), mode of inheritance: AD
• atrial standstill 2 (Limited), mode of inheritance: AR
• atrial fibrillation, familial, 6 (Limited), mode of inheritance: Unknown
• dilated cardiomyopathy (No Known Disease Relationship), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Atrial fibrillation, familial, 6; Atrial standstill 2	AD/AR	Cardiovascular	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	Cardiovascular	6225642; 18614783; 20064500; 20543198; 23275345
The clinical onset of manifestations has been described in the adult period, but earlier surveillance may be beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPPA gene.

• Atrial fibrillation, familial, 6 (111 variants)
• not provided (22 variants)
• not specified (9 variants)
• Atrial fibrillation, familial, 6;Atrial standstill 2 (5 variants)
• Cardiac arrhythmia (1 variants)
• Atrial standstill 2;Atrial fibrillation, familial, 6 (1 variants)
• Vascular dementia (1 variants)
• NPPA-related condition (1 variants)
• Atrial standstill 2 (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPPA gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	25		26
missense			57	6	1	64
nonsense			2			2
start loss						0
frameshift			2			2
inframe indel			5			5
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding				8	15	23
Total	0	0	67	39	16

Variants in NPPA

This is a list of pathogenic ClinVar variants found in the NPPA region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-11845740-TCACTTTCAAAC-T			Benign (Nov 20, 2020)
1-11845794-A-G			Benign (Mar 14, 2021)
1-11845917-A-G			Benign (Mar 14, 2021)
1-11845924-A-G			Benign (Sep 04, 2018)
1-11845938-C-A			Benign (Nov 20, 2020)
1-11846007-CTT-C		Atrial fibrillation, familial, 6	Pathogenic (Jul 10, 2008)
1-11846010-CA-TG		Atrial fibrillation, familial, 6	Uncertain significance (Mar 01, 2023)
1-11846011-A-G		not specified • Atrial fibrillation, familial, 6	Benign (Feb 01, 2024)
1-11846018-C-A		Atrial fibrillation, familial, 6	Likely benign (Sep 17, 2020)
1-11846023-A-C		Atrial fibrillation, familial, 6	Likely benign (Feb 24, 2020)
1-11846030-A-G		Atrial fibrillation, familial, 6	Likely benign (Feb 27, 2022)
1-11846032-A-T		Atrial fibrillation, familial, 6	Likely benign (Nov 07, 2022)
1-11846318-C-CT			Benign (Jun 20, 2021)
1-11846856-C-G			Benign (Sep 04, 2018)
1-11846903-T-C			Benign (Sep 04, 2018)
1-11846911-GC-G			Benign (Aug 13, 2019)
1-11846911-GCC-G			Benign (Nov 20, 2020)
1-11846921-C-CT			Benign (Mar 01, 2019)
1-11846924-T-C			Benign (Sep 04, 2018)
1-11847093-C-T		Atrial fibrillation, familial, 6	Likely benign (Dec 11, 2023)
1-11847096-TC-T		Atrial fibrillation, familial, 6	Benign (Mar 03, 2022)
1-11847097-C-T		Atrial fibrillation, familial, 6	Likely benign (Nov 27, 2023)
1-11847105-C-T		Atrial fibrillation, familial, 6	Likely benign (Sep 29, 2023)
1-11847114-C-T		Atrial standstill 2 • Atrial fibrillation, familial, 6 • not specified	Conflicting classifications of pathogenicity (Jan 13, 2024)
1-11847115-G-A		Atrial fibrillation, familial, 6	Uncertain significance (Oct 31, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPPA	protein_coding	protein_coding	ENST00000376480	3	2637

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000545	0.478	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.266	100	92.8	1.08	0.00000559	976
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000236	0.000235
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000802	0.0000791
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: HIF-1 signaling pathway - Homo sapiens (human);Physiological factors;MicroRNAs in cardiomyocyte hypertrophy;YAP1- and WWTR1 (TAZ)-stimulated gene expression;Cardiac Hypertrophic Response;Cardiac conduction;NO-cGMP-PKG mediated Neuroprotection;corticosteroids and cardioprotection;alk in cardiac myocytes;nfat and hypertrophy of the heart ;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;GPCR signaling-G alpha s Epac and ERK;Cardiac conduction;Muscle contraction;GPCR signaling-G alpha s PKA and ERK;GPCR signaling-G alpha i;AP-1 transcription factor network (Consensus)

Recessive Scores

• pRec: 0.581

Intolerance Scores

• loftool: 0.640
• rvis_EVS: 0.86
• rvis_percentile_EVS: 88.62

Haploinsufficiency Scores

• pHI: 0.0770
• hipred: N
• hipred_score: 0.245
• ghis: 0.420

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Nppa
• Phenotype: renal/urinary system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: response to hypoxia;negative regulation of systemic arterial blood pressure;cGMP biosynthetic process;transcription initiation from RNA polymerase II promoter;protein folding;receptor guanylyl cyclase signaling pathway;neuropeptide signaling pathway;female pregnancy;regulation of blood pressure;positive regulation of heart rate;regulation of signaling receptor activity;positive regulation of cGMP-mediated signaling;cardiac muscle hypertrophy in response to stress;cGMP-mediated signaling;negative regulation of cell growth;response to insulin;response to muscle stretch;cellular protein metabolic process;regulation of blood vessel size;regulation of atrial cardiac muscle cell membrane repolarization;positive regulation of cardiac muscle contraction;cell growth involved in cardiac muscle cell development;cellular response to mechanical stimulus;regulation of high voltage-gated calcium channel activity;positive regulation of delayed rectifier potassium channel activity;regulation of calcium ion transmembrane transport via high voltage-gated calcium channel;positive regulation of histamine secretion by mast cell;positive regulation of potassium ion export across plasma membrane;regulation of cardiac conduction;negative regulation of collecting lymphatic vessel constriction
• Cellular component: extracellular region;extracellular space;nucleus;cytoplasm;protein-containing complex;mast cell granule;perinuclear region of cytoplasm;collagen-containing extracellular matrix
• Molecular function: signaling receptor binding;hormone activity;neuropeptide hormone activity;protein binding;hormone receptor binding;neuropeptide receptor binding