rs145268073

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001243133.2(NLRP3):c.1463G>A(p.Arg488Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,612,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R488W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6O:1

Conservation

PhyloP100: 0.102

Publications

27 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: Benign. The variant received -10 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09971681).

BP6

Variant 1-247424912-G-A is Benign according to our data. Variant chr1-247424912-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97934.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00065 (99/152332) while in subpopulation NFE AF = 0.00125 (85/68036). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.1463G>A	p.Arg488Lys	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.1463G>A	p.Arg488Lys	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

Frequencies

GnomAD3 genomes

AF:

0.000650

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000641

AC:

160

AN:

249698

AF XY:

0.000680

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000980

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.00102

AC:

1489

AN:

1460176

Hom.:

Cov.:

AF XY:

0.000997

AC XY:

724

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

51732

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00127

AC:

1416

AN:

1112000

Other (OTH)

AF:

0.000696

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000650

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41576

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Aug 13, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NLRP3 c.1469G>A; p.Arg490Lys variant (rs145268073), also known as Arg488Lys, is published in the medical literature in several individuals with cryopyrin-associated periodic syndrome (CAPS) as well as unaffected family members (Arostegui 2004, Haverkamp 2014, Kuemmerle-Deschner 2017, Rae 2018, Rowczenio 2013). The variant has been implicated as a low penetrance variant that shows variable expressivity (Kuemmerle-Deschner 2017, Rowczenio 2013). The variant is listed in the ClinVar database (Variation ID: 97934) and in the general population with an allele frequency of 0.07% (188/281,098 alleles) in the Genome Aggregation Database. The arginine at codon 490 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.591). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Arg490Lys variant is uncertain at this time. References: Arostegui JI et al. Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. Arthritis Rheum. 2004 Dec;50(12):4045-50. PMID: 15593220. Haverkamp MH et al. Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). Clin Exp Immunol. 2014 Sep;177(3):720-31. PMID: 24773462. Kuemmerle-Deschner JB et al. Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges. Arthritis Rheumatol. 2017 Nov;69(11):2233-2240. PMID: 28692792. Rae W et al. Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics. Clin Genet. 2018 Mar;93(3):647-655. PMID: 29077208. Rowczenio DM et al. Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature. Arthritis Res Ther. 2013 Feb 19;15(1):R30. PMID: 23421920. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NLRP3: BS1, BS2 -

Jan 30, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in the heterozygous state in non-CAPS (cryopyrin-associated periodic syndromes) individuals with atypical inflammatory symptoms, and in an individual with familial cold autoinflammatory syndrome (FCAS); heterozygous unaffected family members were also detected (PMID: 15593220, 17393462, 24773462); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.(R488K); This variant is associated with the following publications: (PMID: 26984802, 24773462, 17393462, 29922587, 29077208, 28692792, 33329557, 34426522, 33989670, 33207704, 32707200, 30476936, 36586411, 36927399, Blank2021[paper], 35729334, 33401496, 31874111, 35753512, 34596024, 34014414, O'Sullivan2021[paper], 35621220, 19302049, 15593220) -

not specified

Benign:2

Mar 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 1

Benign:1Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

NLRP3-related disorder

Uncertain:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NLRP3 c.1469G>A variant is predicted to result in the amino acid substitution p.Arg490Lys. This variant, previously reported as p.Arg488Lys, has been reported in unaffected individuals, individuals with atypical inflammatory syndrome and an individual with familial cold autoinflammatory syndrome/FACS (Haverkamp et al 2014. PubMed ID: 24773462; Arostegui et al 2004. PubMed ID: 15593220; Kuemmerle-Deschner et al 2017. PubMed ID: 28692792). The c.1469G>A variant has been reported with low penetrance, is found in 0.12% of Non-Finnish Europeans and has been interpreted as likely benign and uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/97934/). Without additional conclusive evidence, the clinical significance of the c.1469G>A (p.Arg490Lys) variant is currently uncertain. -

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C1835697:Keratitis fugax hereditaria;C4521680:Hearing loss, autosomal dominant 34, with or without inflammation;C4551895:Familial cold autoinflammatory syndrome 1

Uncertain:1

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Uncertain:1

Mar 22, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cryopyrin associated periodic syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing impairment

Benign:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1_Strong, BS2_Strong, BP4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;T;T;.;.;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.80

T;.;T;T;.;T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.10

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.34

PhyloP100

0.10

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.2

N;N;N;N;N;.;.;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.038

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

Polyphen

0.36

B;B;B;D;B;.;.;P

Vest4

0.20

MVP

1.0

MPC

1.3

ClinPred

0.055

GERP RS

4.2

Varity_R

0.48

gMVP

0.76

Mutation Taster

=1/99

disease causing

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over