rs180177449
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PP2PP5_ModerateBP4
The NM_001243133.2(NLRP3):c.515T>C(p.Ile172Thr) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
NLRP3
NM_001243133.2 missense
NM_001243133.2 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 0.633
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a strand (size 3) in uniprot entity NLRP3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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.
PP5
Variant 1-247423964-T-C is Pathogenic according to our data. Variant chr1-247423964-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97964.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-247423964-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-247423964-T-C is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.20805335). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NLRP3 | NM_001243133.2 | c.515T>C | p.Ile172Thr | 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.515T>C | p.Ile172Thr | missense_variant | 4/10 | 1 | NM_001243133.2 | ENSP00000337383.4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cryopyrin associated periodic syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 27, 2021 | 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. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with cryopyrin-associated periodic syndrome (PMID: 15231984, Invitae). In at least one individual the variant was observed to be de novo. The variant is also known as p.I172T. ClinVar contains an entry for this variant (Variation ID: 97964). This sequence change replaces isoleucine with threonine at codon 174 of the NLRP3 protein (p.Ile174Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. - |
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
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
.;T;T;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
D;.;T;T;.;D;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;.;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;.;.;D
Sift4G
Uncertain
D;D;D;D;D;.;.;D
Polyphen
B;B;B;B;B;.;.;B
Vest4
MutPred
Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);Loss of stability (P = 0.0016);
MVP
MPC
0.61
ClinPred
T
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