rs180177484

Positions:

• chr1-247424359-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001243133.2(NLRP3):​c.910G>A​(p.Glu304Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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. E304D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 8.94

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001243133.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 1-247424359-G-A is Pathogenic according to our data. Variant chr1-247424359-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424359-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.910G>A	p.Glu304Lys	missense_variant	4/10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.910G>A	p.Glu304Lys	missense_variant	4/10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cryopyrin associated periodic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2021

This variant has been observed in individual(s) with cryopyrin-associated periodic syndrome (PMID: 16920754, 27650144, 21637346). This variant is also known as E304K in the literature. ClinVar contains an entry for this variant (Variation ID: 97981). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 306 of the NLRP3 protein (p.Glu306Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NLRP3 protein function. Experimental studies have shown that this variant affects NLRP3 protein function (PMID: 27548431). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2022

Published functional studies demonstrate a damaging effect due to impairment of the negative regulation activity of the NLRP3 protein (Mortimer et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25883259, 28424701, 20472245, 16920754, 23442610, 21637346, 27650144, 33020839, 33329557, 19302049, 27548431) -

Familial cold autoinflammatory syndrome 1 Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.76
Sift	Benign	0.045	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.054	T;T;T;T;T;.;.;T
Polyphen		1.0	D;D;D;D;D;.;.;D
Vest4		0.88
MutPred		0.96		Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);Gain of ubiquitination at E306 (P = 0.0337);
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.86
gMVP		0.97

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: rs180177484; hg19: chr1-247587661;