NRP1

protein-coding

neuropilin 1, the group of CD molecules

Gene summary

This gene encodes one of two neuropilins, which contain specific protein domains which allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contains a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors; they affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members. This protein has also been determined to act as a co-receptor for SARS-CoV-2 (which causes COVID-19) to infect host cells. [provided by RefSeq, Nov 2020]

MANE transcript

NM_003873.7

Inheritance

ClinVar variants

U:302B:132

Top phenotype

NRP1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr10:33,177,492-33,336,262

External References & Databases

Ensembl (ENSG00000099250)

Transcript & Mutation Effects

hg38 • Region Span ~158.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005453

Submitter: ClinGen

NRP1 was first reported in relation to autosomal recessive congenital heart disease in 2015 (Shaheen et al., PMID: 25713110). One variant (frameshift) that has been reported in one proband with persistent truncus arteriosus in one publication (PMID: 25713110) is included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (a mouse model; PMID: 12852851). In the mouse model, the mutant mice exhibit ventricular septal defect, persistent truncus arteriosus, and anomalous origin of the coronary arteries. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 3/5/2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NRP1 variants in ClinVar

3 Conditions Cataloged

NRP1-related disorderTotal: 399

not specifiedTotal: 112

not providedTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003873.7. 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			3 clinvar	109 clinvar	7 clinvar	119
missense			285 clinvar	13 clinvar	3 clinvar	301
nonsense			6 clinvar			6
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	302	122	10	434

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 93 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003873.7	RefSeq	NP_003864.5	17	MANE Select
ENST00000374867.7	Ensembl	ENSP00000364001.2	17	MANE Select
NM_001024628.3	RefSeq	NP_001019799.2	12	Standard
NM_001024629.3	RefSeq	NP_001019800.2	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nrp1b	Danio rerio	Structure: mid cerebral vein Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

nrp1b

Danio rerio

Structure: mid cerebral vein

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HTLV-I infection - Homo sapiens (human)
Axon guidance - Homo sapiens (human)
VEGF Signaling Pathway
Angiogenesis overview
miR-targeted genes in epithelium - TarBase

Biological Process

angiogenesis
branching involved in blood vessel morphogenesis
neuron migration
positive regulation of endothelial cell proliferation
sprouting angiogenesis

Molecular Function

vascular endothelial growth factor-activated receptor activity
GTPase activator activity
protein binding
heparin binding
coreceptor activity

Cellular Component

semaphorin receptor complex
extracellular space
early endosome
cytosol
neurofilament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265371
Coding exons: 17
Length: 158771
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.56	434	536	0.810	0.0000293	6089
Missense (PolyPhen)		160	243.3	0.65762		2666
Synonymous	-0.325	206	200	1.03	0.0000121	1731
Loss of Function	5.36	8	48.2	0.166	0.00000263	535

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The membrane-bound isoform 1 is a receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF165 isoform of VEGFA and VEGFB. Coexpression with KDR results in increased VEGF165 binding to KDR as well as increased chemotaxis. Regulate VEGF-induced angiogenesis. Binding to VEGFA initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). {ECO:0000250|UniProtKB:P97333}.;

Recessive Scores

pRec: 0.319

Intolerance Scores

LoFtool: 0.0615
RVIS EVS: -0.48
RVIS percentile EVS: 22.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.983

Gene Damage Prediction

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