rs180177456

Positions:

• chr1-247424426-G-A
• chr1-247424426-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_001243133.2(NLRP3):​c.977G>A​(p.Gly326Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G326A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 3.17

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 Uncertain_significance. Variant got 5 ACMG points.

• 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.
• PP5: Variant 1-247424426-G-A is Pathogenic according to our data. Variant chr1-247424426-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97992.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-247424426-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.977G>A	p.Gly326Glu	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.977G>A	p.Gly326Glu	missense_variant	4/10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryopyrin associated periodic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 11, 2019

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine with glutamic acid at codon 328 of the NLRP3 protein (p.Gly328Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with cryopyrin-associated periodic syndrome (CAPS) in a family (PMID: 30338413), and has been observed in several unrelated individuals affected with clinical features of CAPS (PMID: 15724022, 24773462, Invitae). This variant is also known as G326E in the literature. ClinVar contains an entry for this variant (Variation ID: 97992). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T;T;.;.;.;.;.
Eigen	Benign	0.094
Eigen_PC	Benign	-0.00063
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.96	N;N;N;N;N;.;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.087	T;T;T;T;T;.;.;T
Sift4G	Benign	0.11	T;T;T;T;T;.;.;T
Polyphen		0.93	P;D;D;D;P;.;.;D
Vest4		0.83
MutPred		0.70		Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);Gain of methylation at K324 (P = 0.0395);
MVP		0.98
MPC		1.5
ClinPred		0.72	D
GERP RS		3.1
Varity_R		0.35
gMVP		0.92

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: rs180177456; hg19: chr1-247587728; COSMIC: COSV105198055;