rs180177449

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

Scores

7
11

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 0.633
Variant links:
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]

Genome browser will be placed here

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
NLRP3NM_001243133.2 linkuse as main transcriptc.515T>C p.Ile172Thr missense_variant 4/10 ENST00000336119.8 NP_001230062.1 Q96P20A0A7I2R3P8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NLRP3ENST00000336119.8 linkuse as main transcriptc.515T>C p.Ile172Thr missense_variant 4/101 NM_001243133.2 ENSP00000337383.4 A0A7I2R3P8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 27, 2021This 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 providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
18
DANN
Benign
0.95
DEOGEN2
Uncertain
0.44
.;T;T;.;.;.;.;.
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.85
D;.;T;T;.;D;T;T
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.21
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.70
T
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.5
N;N;N;N;N;.;.;N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0040
D;D;D;D;D;.;.;D
Sift4G
Uncertain
0.015
D;D;D;D;D;.;.;D
Polyphen
0.0040
B;B;B;B;B;.;.;B
Vest4
0.63
MutPred
0.44
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
0.99
MPC
0.61
ClinPred
0.16
T
GERP RS
3.1
Varity_R
0.31
gMVP
0.29

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs180177449; hg19: chr1-247587266; API