1-247424912-G-A

Position:

chr1-247424912-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_ModerateBS1BS2

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:5B:4O:1

Conservation

PhyloP100: 0.102

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 -9 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=0.09971681).

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	Protein	UniProt
NLRP3	NM_001243133.2 linkuse as main transcript	c.1463G>A	p.Arg488Lys	missense_variant	4/10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 linkuse as main transcript	c.1463G>A	p.Arg488Lys	missense_variant	4/10	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

GnomAD3 exomes

AF:

0.000641

AC:

160

AN:

249698

Hom.:

AF XY:

0.000680

AC XY:

AN XY:

135224

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 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.:

Cov.:

AF XY:

0.000997

AC XY:

724

AN XY:

726518

show subpopulations

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:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74480

show subpopulations

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.:

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:5Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

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. -
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	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	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, 36586411, 36927399, Blank2021[paper], 35729334, 33401496, 31874111, 35753512, 34596024, 34014414, O'Sullivan2021[paper], 35621220, 19302049, 15593220) -

Familial cold autoinflammatory syndrome 1

Benign:1Other: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. -

NLRP3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

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

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

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