rs121908149
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001243133.2(NLRP3):c.1055C>T(p.Ala352Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A352T) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
NLRP3
NM_001243133.2 missense
NM_001243133.2 missense
Scores
7
9
1
Clinical Significance
Conservation
PhyloP100: 5.36
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 19 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001243133.2
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr1-247424503-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, NLRP3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
?
Variant 1-247424504-C-T is Pathogenic according to our data. Variant chr1-247424504-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424504-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP3 | NM_001243133.2 | c.1055C>T | p.Ala352Val | missense_variant | 4/10 | ENST00000336119.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP3 | ENST00000336119.8 | c.1055C>T | p.Ala352Val | 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/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cryopyrin associated periodic syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 12, 2020 | This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala354 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 26931528), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect NLRP3 protein function (PMID: 19501000, 29322034). This variant has been observed to segregate with Muckle-Wells syndrome in a family and has been reported in unrelated individuals affected with cryopyrin-associated periodic syndrome (PMID: 11687797, 30431487, 21109514, 29047407). This variant is also known as p.Ala352Val in the literature. ClinVar contains an entry for this variant (Variation ID: 4373). This sequence change replaces alanine with valine at codon 354 of the NLRP3 protein (p.Ala354Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Familial amyloid nephropathy with urticaria AND deafness Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;.;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;.;D
Sift4G
Uncertain
D;D;D;D;D;.;.;D
Polyphen
D;D;D;D;D;.;.;D
Vest4
MutPred
Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);Gain of methylation at K357 (P = 0.1124);
MVP
MPC
1.3
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