rs151344629
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001243133.2(NLRP3):c.1043C>T(p.Thr348Met) variant causes a missense change involving the alteration of a non-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 (★★). Synonymous variant affecting the same amino acid position (i.e. T348T) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Consequence
NLRP3
NM_001243133.2 missense
NM_001243133.2 missense
Scores
10
5
2
Clinical Significance
Conservation
PhyloP100: 2.71
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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, 0.939
PP5
?
Variant 1-247424492-C-T is Pathogenic according to our data. Variant chr1-247424492-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424492-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP3 | NM_001243133.2 | c.1043C>T | p.Thr348Met | missense_variant | 4/10 | ENST00000336119.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP3 | ENST00000336119.8 | c.1043C>T | p.Thr348Met | missense_variant | 4/10 | 1 | NM_001243133.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 42
GnomAD4 exome
Cov.:
42
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | 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: 27435956, 14630794, 21356079, 26531310, 27353043, 23442610, 17178739, 25730877, 34979568, 31816408, 33042144, 20472245, 25349319, 24952504, 26931528, 11992256, 28028683, 28501347, 25596455, 16100350, 26245507, 30184330, 30273710, 23486414, 15593220, 32152129, 34099780) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | NLRP3: PP1:Strong, PM1, PM2, PS4:Moderate, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 24, 2018 | The NLRP3 c.1049C>T;p.Thr350Met (rs151344629), also known as Thr348Met, is published in the literature in individuals with various periodic fever syndromes (Kuemmerle-Deschner 2011, Kuemmerle-Deschner 2015). The variant has been described both as occurring de novo and as segregating with disease (Dode 2002, Kanariou 2014). The variant is listed as pathogenic in the ClinVar database (Variation ID: 97909). The variant is not listed in the general population databases (Exome Variant Server, Exome Aggregation Consortium), indicating it is not a common polymorphism. The threonine at codon 350 is moderately conserved across a variety of species and computational programs (Align GVGD, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. Pathogenic NLRP3 variants are causative for autosomal dominant Muckle-Wells syndrome (MIM#606416). References: Dode C et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002 70(6):1498-506. Kanariou M et al. Successful management of cryopyrin-associated periodic syndrome with canakinumab in infancy. Pediatrics. 2014 134(5):e1468-73. Kuemmerle-Deschner JB et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1B mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011 13(1):R34. Kuemmerle-Deschner JB et al. Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J. 2015 13(1):43. - |
Cryopyrin associated periodic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 16100350, 25730877). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 97909). This variant is also known as p.Thr348Met. This missense change has been observed in individual(s) with clinical features of NLRP3-related conditions (PMID: 11992256, 16100350, 17178739, 20472245, 21356079, 23442610, 25730877, 26245507, 26531310, 26931528). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 350 of the NLRP3 protein (p.Thr350Met). - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 15, 2021 | - - |
Familial amyloid nephropathy with urticaria AND deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Aug 11, 2014 | - - |
Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;.;.;D
REVEL
Pathogenic
Sift
Benign
T;T;T;T;T;.;.;T
Sift4G
Pathogenic
D;D;D;D;D;.;.;D
Polyphen
D;D;D;D;D;.;.;D
Vest4
MutPred
Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at