rs121908153

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001243133.2(NLRP3):c.907G>A(p.Asp303Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D303A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.13

Publications

100 publications found

Variant links:

Genes affected

NLRP3 (HGNC:16400): (NLR family pyrin domain containing 3) This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. The SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via the formation of ion channels in macrophages. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), keratoendotheliitis fugax hereditarian, and deafness, autosomal dominant 34, with or without inflammation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Aug 2020]

NLRP3 Gene-Disease associations (from GenCC):

CINCA syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
cryopyrin-associated periodic syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
familial cold autoinflammatory syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
familial cold autoinflammatory syndrome 1
Inheritance: AD Classification: STRONG Submitted by: G2P
Muckle-Wells syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
keratitis fugax hereditaria
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NLRP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001243133.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-247424357-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3381130.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the NLRP3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.1417 (below the threshold of 3.09). Trascript score misZ: 3.5037 (above the threshold of 3.09). GenCC associations: The gene is linked to CINCA syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome, cryopyrin-associated periodic syndrome, keratitis fugax hereditaria.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 1-247424356-G-A is Pathogenic according to our data. Variant chr1-247424356-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.907G>A	p.Asp303Asn	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.907G>A	p.Asp303Asn	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Jan 30, 2014

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted c.913 G>A at the cDNA level or p.Asp305Asn (D305N) at the protein level. Please note that this mutation is also referred to as D303N due to a difference in the convention of naming the first codon of the NLRP3 gene. The D305N missense mutation in the NLRP3 gene has been previously reported in association with Muckle-Wells syndrome (Dode et al, 2002) and CINCA syndrome (Neven et al., 2004). Therefore, its presence is consistent with a diagnosis of a cryopyrin-associated disease. -

Apr 18, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PS3, PP3, PS4, PM2_SUP -

Oct 25, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NLRP3 c.913G>A;p.Asp305Asn (also known as Asp303Asn) variant is published in the medical literature in individuals with Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease (NOMID) (Dode 2002, Eungdamrong 2013, Feldmann 2002,Haverkamp 2014). Additionally, a mouse model with this variant recapitulates the disease (Qu 2015). The variant is listed in the ClinVar database (Variation ID: 4377), and in the dbSNP variant database (rs121908153), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The aspartic acid at codon 305 is well conserved across mammals and computational programs (PolyPhen2, SIFT) predict this variant to be deleterious. Taken together, this variant is considered pathogenic. Pathogenic NLRP3 variants are associated with CINCA syndrome (MIM#607115), familial cold-induced inflammatory syndrome (MIM#120100), and Muckle-Wells syndrome (MIM#191900). References: Dode C et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002 70(6):1498-506. Eungdamrong J et al. Muckle-Wells treatment with anakinra. Dermatol Online J. 2013 19(12):20720. Feldmann J et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet.2002 71(1):198-203. Haverkamp MH et al. Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). Clin Exp Immunol. 2014 177(3):720-31. Qu C et al. NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J. 2015 29(4):1269-79. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cryopyrin associated periodic syndrome

Pathogenic:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 305 of the NLRP3 protein (p.Asp305Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NLRP3-associated conditions, including Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease, with evidence of disease co-segregation (PMID: 11992256, 24365011, 24773462, 25766347, 26590045). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as G907A D303N. ClinVar contains an entry for this variant (Variation ID: 4377). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NLRP3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 15020601, 22193915, 24517500). This variant disrupts the p.Asp305 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 14630794, 21702021), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Familial amyloid nephropathy with urticaria AND deafness

Pathogenic:1

Jul 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Chronic infantile neurological, cutaneous and articular syndrome

Pathogenic:1

Jul 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Familial cold autoinflammatory syndrome 1

Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;D;D;.;.;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.;D;D;.;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

PhyloP100

7.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.8

D;D;D;D;D;.;.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0050

D;D;D;D;D;.;.;D

Sift4G

Uncertain

0.011

D;D;D;D;D;.;.;D

Polyphen

1.0

D;D;D;D;D;.;.;D

Vest4

0.77

MutPred

0.95

Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);Gain of MoRF binding (P = 0.2672);

MVP

1.0

MPC

1.3

ClinPred

0.99

GERP RS

4.0

Varity_R

0.60

gMVP

0.89

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over