NPR1

protein-coding

natriuretic peptide receptor 1, the group of Transmembrane guanylate cyclases

Gene summary

Guanylyl cyclases, catalyzing the production of cGMP from GTP, are classified as soluble and membrane forms (Garbers and Lowe, 1994 [PubMed 7982997]). The membrane guanylyl cyclases, often termed guanylyl cyclases A through F, form a family of cell-surface receptors with a similar topographic structure: an extracellular ligand-binding domain, a single membrane-spanning domain, and an intracellular region that contains a protein kinase-like domain and a cyclase catalytic domain. GC-A and GC-B function as receptors for natriuretic peptides; they are also referred to as atrial natriuretic peptide receptor A (NPR1) and type B (NPR2; MIM 108961). Also see NPR3 (MIM 108962), which encodes a protein with only the ligand-binding transmembrane and 37-amino acid cytoplasmic domains. NPR1 is a membrane-bound guanylate cyclase that serves as the receptor for both atrial and brain natriuretic peptides (ANP (MIM 108780) and BNP (MIM 600295), respectively).[supplied by OMIM, May 2009]

Previous symbols:

ANPRA
NPRA

MANE transcript

NM_000906.4

Inheritance

ClinVar variants

U:108B:10

Top phenotype

genetic hypertension

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr1:153,678,688-153,693,992

External References & Databases

Ensembl (ENSG00000169418)

Transcript & Mutation Effects

hg38 • Region Span ~15.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic hypertensionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015512

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NPR1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 101

not providedTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000906.4. 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 clinvar	5 clinvar	2 clinvar	8
missense			103 clinvar	2 clinvar	1 clinvar	106
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	108	7	3	118

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000906.4	RefSeq	NP_000897.3	22	MANE Select
ENST00000368680.4	Ensembl	ENSP00000357669.3	22	MANE Select
ENST00000908786.1	Ensembl	ENSP00000578845.1	22	Standard
ENST00000908787.1	Ensembl	ENSP00000578846.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aldosterone synthesis and secretion - Homo sapiens (human)
Regulation of lipolysis in adipocytes - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)

Biological Process

cGMP biosynthetic process
protein phosphorylation
signal transduction
cell surface receptor signaling pathway
receptor guanylyl cyclase signaling pathway

Molecular Function

peptide receptor activity
guanylate cyclase activity
protein kinase activity
ATP binding
GTP binding

Cellular Component

plasma membrane
integral component of membrane
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368680
Coding exons: 22
Length: 15356
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.82	414	610	0.679	0.0000358	6776
Missense (PolyPhen)		143	274.68	0.5206		3109
Synonymous	1.29	231	257	0.898	0.0000146	2216
Loss of Function	4.49	16	50.3	0.318	0.00000249	555

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for the atrial natriuretic peptide NPPA/ANP and the brain natriuretic peptide NPPB/BNP which are potent vasoactive hormones playing a key role in cardiovascular homeostasis. Has guanylate cyclase activity upon binding of the ligand. {ECO:0000269|PubMed:1672777}.;

Recessive Scores

pRec: 0.318

Intolerance Scores

LoFtool: 0.186
RVIS EVS: -0.24
RVIS percentile EVS: 36.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.968

Gene Damage Prediction

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