rs145268073

Positions:

• chr1-247424912-G-A
• chr1-247424912-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Moderate BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4 O:1
• Conservation: PhyloP100: 0.102

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NLRP3
• BP4: Computational evidence support a benign effect (MetaRNN=0.09971681).
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2	c.1463G>A	p.Arg488Lys	missense_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8	c.1463G>A	p.Arg488Lys	missense_variant	4/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152214 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000641 AC: 160 AN: 249698 Hom.: 0 AF XY: 0.000680 AC XY: 92 AN XY: 135224

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 SAS 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.: 0 Cov.: 38 AF XY: 0.000997 AC XY: 724 AN XY: 726518

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000967

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74480

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.000623

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000818

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NLRP3: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2023	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 supports 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, 36586411, 36927399, Blank2021[paper], 35729334, 33401496, 31874111, 35753512, 34596024, 34014414, O'Sullivan2021[paper], 35621220, 19302049, 15593220) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 10, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2020	- -

Familial cold autoinflammatory syndrome 1 Benign:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 22, 2021

- -

Cryopyrin associated periodic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hearing impairment Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 12, 2021

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	T
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	14
DANN	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.80	T;.;T;T;.;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
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	T
GERP RS		4.2
Varity_R		0.48
gMVP		0.76

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

Other links and lift over

dbSNP: rs145268073; hg19: chr1-247588214; COSMIC: COSV105198051;