rs180177470

chr1-247424380-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001243133.2(NLRP3):c.931G>A(p.Glu311Lys) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 3.63

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 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001243133.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NLRP3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 1-247424380-G-A is Pathogenic according to our data. Variant chr1-247424380-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424380-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2	c.931G>A	p.Glu311Lys	missense_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8	c.931G>A	p.Glu311Lys	missense_variant	4/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 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

Invitae

Oct 28, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 313 of the NLRP3 protein (p.Glu313Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NLRP3-related conditions (PMID: 22146561, 27191192). It has also been observed to segregate with disease in related individuals. This variant is also known as E311K. ClinVar contains an entry for this variant (Variation ID: 97987). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2020

- -

Familial amyloid nephropathy with urticaria AND deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 07, 2022

- -

Familial cold autoinflammatory syndrome 1 Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	0.79	D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;.;.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.012	D;D;D;D;D;.;.;D
Polyphen		0.88	P;P;P;D;P;.;.;D
Vest4		0.74
MutPred		0.70		Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);Gain of ubiquitination at E313 (P = 0.0162);
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.81
gMVP		0.82

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: rs180177470; hg19: chr1-247587682; COSMIC: COSV60219989;