NLRP4

protein-coding

NLR family pyrin domain containing 4, the group of NLR family|Pyrin domain containing

Gene summary

The protein encoded by this gene is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family, and is predicted to contain an N-terminal pyrin effector domain (PYD), a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). This gene product has a demonstrated role as a negative regulator of autophagy and type I interferon signaling pathways as a result of protein interactions with its NACHT domain. The PYD domain has also been shown to be important in the inhibition of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells). [provided by RefSeq, Dec 2016]

Previous symbols:

NALP4

MANE transcript

NM_134444.5

Inheritance

—

ClinVar variants

U:143B:19

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr19:55,836,540-55,881,855

External References & Databases

Ensembl (ENSG00000160505)

Transcript & Mutation Effects

hg38 • Region Span ~45.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NLRP4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 147

not providedTotal: 20

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_134444.5. 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	3 clinvar	1 clinvar	5
missense			139 clinvar	14 clinvar	1 clinvar	154
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	143	17	2	162

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_134444.5	RefSeq	NP_604393.2	9	MANE Select
ENST00000301295.11	Ensembl	ENSP00000301295.4	9	MANE Select
ENST00000587464.1	Ensembl	ENSP00000468496.1	2	Standard
ENST00000587891.5	Ensembl	ENSP00000465463.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide-binding Oligomerization Domain (NOD) pathway
IRF3 mediated activation of type 1 IFN
ZBP1(DAI) mediated induction of type I IFNs
STING mediated induction of host immune responses
Regulation of innate immune responses to cytosolic DNA

Biological Process

inflammatory response
regulation of type I interferon production

Molecular Function

ATP binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301295
Coding exons: 9
Length: 45277
Individuals with no LoFs: 125443
Homozygous LoFs: 1
Heterozygous LoFs: 304
Defined: 125748
p: 0.00121

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.737	600	551	1.09	0.0000319	6575
Missense (PolyPhen)		108	118.65	0.91022		1595
Synonymous	-3.64	301	231	1.30	0.0000150	1872
Loss of Function	2.64	20	37.4	0.534	0.00000177	474

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0018	0.0015	notable
Latino/Admixed American	0.00047	0.00043	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0010	0.00092	notable
Finnish	0.00083	0.00083	rare
European (Non-Finnish)	0.0016	0.0015	notable
South Asian	0.0017	0.0017	notable
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in inflammation and recognition of cytosolic pathogen-associated molecular patterns (PAMPs) not intercepted by membrane-bound receptors. Acts as a negative regulator of the type I interferon signaling pathway by serving as an adapter to promote DTX4-mediated ubiquitination of activated TBK1, and its subsequent degradation. Suppresses NF-kappaB induction by the cytokines TNFA and IL1B, suggesting that it operates at a point of convergence in these two cytokine signaling pathways. {ECO:0000269|PubMed:12093792, ECO:0000269|PubMed:22388039}.;

Recessive Scores

pRec: 0.0970

Intolerance Scores

LoFtool: 0.141
RVIS EVS: 0.22
RVIS percentile EVS: 67.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.408

Gene Damage Prediction

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