JAGN1

protein-coding

jagunal homolog 1

Gene summary

The protein encoded by this gene is a transmembrane protein. It functions in the early secretory pathway and is necessary for neutrophil differentiation and survival. Mutations in this gene result in severe congenital neutropenia. [provided by RefSeq, Oct 2014]

MANE transcript

NM_032492.4

Inheritance

ClinVar variants

P:9U:84B:46

Top phenotype

Neutropenia, severe congenital, 6, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr3:9,890,574-9,894,349

External References & Databases

Ensembl (ENSG00000171135)

Transcript & Mutation Effects

hg38 • Region Span ~3.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive severe congenital neutropenia due to JAGN1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014456

Submitter: Orphanet

autosomal recessive severe congenital neutropenia due to JAGN1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014456

Submitter: PanelApp Australia

autosomal recessive severe congenital neutropenia due to JAGN1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014456

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive severe congenital neutropenia due to JAGN1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014456

Submitter: G2P

Clinical Genomic Database (CGD)

Neutropenia, severe congenital, 6, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may sufffer from severe, recurrent bacterial infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BMT has been reported

Refs: 25129144

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to JAGN1 variants in ClinVar

7 Conditions Cataloged

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiencyTotal: 132

Inborn genetic diseasesTotal: 28

not providedTotal: 17

Severe congenital neutropeniaTotal: 8

not specifiedTotal: 6

JAGN1-related disorderTotal: 4

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032492.4. 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				40 clinvar	2 clinvar	42
missense	1 clinvar	4 clinvar	77 clinvar	3 clinvar		85
nonsense	1 clinvar	1 clinvar	1 clinvar			3
start loss		1 clinvar		1 clinvar		2
frameshift		1 clinvar	5 clinvar			6
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	7	84	44	2	139

Highest pathogenic variant AF is 0.000018661776

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032492.4	RefSeq	NP_115881.3	2	MANE Select
ENST00000647897.1	Ensembl	ENSP00000496942.1	2	MANE Select
NM_001363890.1	RefSeq	NP_001350819.1	1	Standard
ENST00000489724.2	Ensembl	ENSP00000497724.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

neutrophil mediated immunity
exocytosis
endoplasmic reticulum organization
protein transport
vesicle-mediated transport

Molecular Function

protein binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307768
Coding exons: 2
Length: 3796
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125747
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0582	103	105	0.984	0.00000557	1191
Missense (PolyPhen)		20	24.081	0.83053		289
Synonymous	-0.844	49	42.0	1.17	0.00000232	362
Loss of Function	0.973	4	6.72	0.595	2.90e-7	75

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Endoplasmic reticulum transmembrane protein involved in vesicle-mediated transport, which is required for neutrophil function. Required for vesicle-mediated transport; it is however unclear whether it is involved in early secretory pathway or intracellular protein transport. Acts as a regulator of neutrophil function, probably via its role in vesicle-mediated transport: required for defense against fungal pathogens and for granulocyte colony-stimulating factor (GM-CSF) signaling pathway; possibly by regulating glycosylation and/or targeting of proteins contributing to the viability and migration of neutrophils. {ECO:0000269|PubMed:25129144, ECO:0000305}.;

Intolerance Scores

LoFtool: 0.383
RVIS EVS: 0.15
RVIS percentile EVS: 64.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.259

Gene Damage Prediction

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