rs121908147

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_001243133.2(NLRP3):c.592G>A(p.Val198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,614,016 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0073 ( 10 hom., cov: 31)

Exomes 𝑓: 0.0085 ( 62 hom. )

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:9O:2

Conservation

PhyloP100: -0.254

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLRP3. . Gene score misZ 2.1417 (greater than the threshold 3.09). Trascript score misZ 3.5037 (greater than threshold 3.09). GenCC has associacion of gene with familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.03694403).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00726 (1104/152162) while in subpopulation NFE AF= 0.00866 (589/68004). AF 95% confidence interval is 0.00808. There are 10 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2 linkuse as main transcript	c.592G>A	p.Val198Met	missense_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8 linkuse as main transcript	c.592G>A	p.Val198Met	missense_variant	4/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes

AF:

0.00726

AC:

1104

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00662

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00541

Gnomad FIN

AF:

0.0255

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00867

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00832

AC:

2089

AN:

251192

Hom.:

AF XY:

0.00851

AC XY:

1156

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00614

Gnomad FIN exome

AF:

0.0232

Gnomad NFE exome

AF:

0.00928

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00853

AC:

12464

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00846

AC XY:

6153

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00416

Gnomad4 ASJ exome

AF:

0.0115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00630

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.00866

Gnomad4 OTH exome

AF:

0.00782

GnomAD4 genome

AF:

0.00726

AC:

1104

AN:

152162

Hom.:

Cov.:

AF XY:

0.00789

AC XY:

587

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00661

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00541

Gnomad4 FIN

AF:

0.0255

Gnomad4 NFE

AF:

0.00866

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00783

Hom.:

Bravo

AF:

0.00567

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.00823

AC:

999

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00802

EpiControl

AF:

0.0104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:9Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 12, 2022	BS1, BS2, BP4, PS4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	The NLRP3 c.598G>A; p.Val200Met variant (rs121908147), also known as V198M, is listed in the Genome Aggregation Database with an allele frequency of up to 2.3% (588/25096 alleles, including 6 homozygotes) in the European Finnish population. The valine at codon 200 is weakly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.222). The variant is listed in the ClinVar database with conflicting classifications (Variation ID: 4371). This variant is reported in the medical literature in individuals with familial cold-induced autoinflammatory syndrome (FCAS) (MIM:120100) and Muckle-Wells syndrome (MWS) (MIM:191900), both also known as cryopyrin-associated periodic syndromes (CAPS), as well as in patients with other autoinflammatory syndromes, acquired disorders including Schnitzler syndrome, and also in asymptomatic carriers (Aganna 2002, Hoffman 2001, Kuemmerle-Deschner 2017, Rowczenio 2013, Torres 2018, Yuksel 2014). Since p.Val200Met presents with variable expressivity and reduced penetrance, this variant may contribute to the inflammatory diseases processes together with other, presently unidentified, genetic and environmental factors. However, the existence of individuals homozygous for the variant in control databases and the high population frequency suggest this variant is benign. Due to conflicting information, the clinical significance of the p.Val200Met variant is uncertain at this time. References: Aganna E et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002 46(9):2445-2452. PMID: 12355493 Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflamatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 29(3):301-305. PMID: 11687797 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. 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 15(1):R30. PMID: 23421920 Torres A et al. De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome. Mol Genet Metab Rep. 2018 Jun 15;16:23-29. PMID: 29922587. Yuksel S. et al. Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behcet’s syndrome patients. Int Immunol. 2014 26(2):71-81. PMID: 24135410. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NLRP3: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	Published functional studies demonstrate that the V200M variant results in moderate increase of interleukin-1 beta secretion, and NLRP3/cryopyrin inflammosome activation (Yuksel et al., 2014); Is considered by some as a risk allele or variant with reduced penetrance (Aksentijevich et al., 2007; Yuksel et al., 2014; Kuemmerle-Deschner et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24123366, 26531310, 30407166, 17393462, 24135410, 25988833, 23421920, 12355493, 20159265, 26020059, 25596455, 15334488, 11687797, 17038455, 22566169, 27994174, 29159471, 29922587, 28692792, 31858722, 30783801, 31036385, 31769854, 31410474, 14872505) -

Familial cold autoinflammatory syndrome 1

Pathogenic:1Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C4551895:Familial cold autoinflammatory syndrome 1

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Feb 13, 2020	NLRP3 NM_004895.4 exon 3 p.Val200Met (c.598G>A): This variant has been reported in the literature in the heterozygous and double heterozygous state in several individuals with clinical features consistent with NLRP3 related abnormal inflammatory response (e.g. Familial Cold Autoinflammatory Syndrome, Muckle-Wells syndrome) (Hoffman 2001 PMID:11687797, Aganna 2002 PMID:12355493, Loock 2010 PMID:20159265, Yuksel 2014 PMID:24135410, Kemmerle-Deschner 2015 PMID:26531310, Neocleous 2016 PMID: 27994174). In some reports, the variant also segregated in other family members with variable clinical features of disease. However, this variant is present in 2.4% (588/25096) of Finnish alleles, including 6 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-247587343-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar with several discrepant classifications from "Benign to Variant of Uncertain Significance" (Variation ID:4371). This variant amino acid Methionine (Met) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest that this variant will impact the protein NLRP3/cryopyrin inflammosome (Yuksel 2014 PMID:24135410); however, further studies are needed to understand its impact. Of note, at least 2 authors in the literature suggest that this variant may act as a risk allele or low penetrance variant (Aganna 2002 PMID:12355493, Yuksel 2014 PMID:24135410). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Kidney disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 02, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 13, 2022

NLRP3 NM_004895.4 exon3 p.Val200Met (c.598G>A): This variant has been reported in the literature in the heterozygous and double heterozygous state in several individuals with clinical features consistent with NLRP3 related abnormal inflammatory response (e.g. Familial Cold Autoinflammatory Syndrome, Muckle-Wells syndrome) (Hoffman 2001 PMID:11687797, Aganna 2002 PMID:12355493, Loock 2010 PMID:20159265, Yuksel 2014 PMID:24135410, Kemmerle-Deschner 2015 PMID:26531310, Neocleous 2016 PMID: 27994174). In some reports, the variant also segregated in other family members with variable clinical features of disease. However, this variant is present in 2.4% (613/25766) of Finnish alleles, including 6 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121908147). This variant is present in ClinVar with several discrepant classifications from "Benign to Variant of Uncertain Significance" (Variation ID:4371). This variant amino acid Methionine (Met) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest that this variant will impact the protein NLRP3/cryopyrin inflammosome (Yuksel 2014 PMID:24135410); however, further studies are needed to understand its impact. Of note, at least 2 authors in the literature suggest that this variant may act as a risk allele or low penetrance variant (Aganna 2002 PMID:12355493, Yuksel 2014 PMID:24135410). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 25, 2022

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2018

p.Val200Met in exon 5 of NLRP3: This variant (also reported as p.Val198Met) is n ot expected to have clinical significance because it has been identified in 0.85 % (2343/276948) of the total chromosomes in the Genome Aggregation Database incl uding 19 homozygotes. The highest allele frequency was 2.38% (613/25766) of Fin nish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908147). The NLRP3 gene is associated with cryopyrin associated periodic syndrome (CAPS) which has an estimated prevalence of 1 in 36 0,000 (Orphanet, http://www.orpha.net, Orpha # 208650). While this variant has been reported in many individuals with features of CAPS and has been reported as a "low-penetrance allele", the variant was also identified in controls and unaf fected family members (Aggana 2002, Rowczenio 2013, Hoffman 2001, Look 2010, Lev y 2015). Furthermore, the frequency of the variant in the affected individuals in several studies was similar to the frequency of the variant in the Genome Agg regation Database (Kone-Paut 2007, Jesus 2012, Rowczenio 2013, Schuh 2015). One study found that in transfected embryonal kidney cells with the p.Val200Met var iant, IL-1? secretion was significantly increased compared to wild-type transfe cted cells (Yuksel 2014). However, another study found that patients with Val19 8Met and other variants described as low-penetrance alleles had similar response s as controls to inflammasome stimulation, compared with patients with clearly p athogenic NLRP3 variants (Rieber 2015). Furthermore, the valine (Val) residue a t position 200 is not conserved through species with >10 mammals having a methio nine (Met) at this position. In summary, due to the high frequency of the varia nt in the general population compared to the low estimated prevalence of CAPS, a nd the absence of enrichment of the variant in affected individuals, this varian t is likely benign. ACMG/AMP criteria applied: BS1, BS4, BP4. -

Cryopyrin associated periodic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

NLRP3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cold autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hearing loss, autosomal dominant 34, with or without inflammation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.43

DANN

Benign

0.73

DEOGEN2

Benign

0.38

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

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.63

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

MetaRNN

Benign

0.037

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

MetaSVM

Benign

-0.73

MutationTaster

Benign

3.0e-11

A;A;A;A;A;A

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.22

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

REVEL

Benign

0.22

Sift

Benign

0.15

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

Sift4G

Benign

0.23

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

Polyphen

0.069

B;B;B;B;B;.;.;B

Vest4

0.070

MVP

0.51

MPC

0.46

ClinPred

0.0057

GERP RS

-7.4

Varity_R

0.039

gMVP

0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over