rs180177449

Positions:

• chr1-247423964-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP5_Moderate BP4

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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

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

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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

Other links and lift over

dbSNP: rs180177449; hg19: chr1-247587266;