rs180177445

Variant names:

• chr1-247424662-A-C
• rs180177445
• NM_001243133.2:c.1213A>C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001243133.2(NLRP3):​c.1213A>C​(p.Thr405Pro) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.07

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a helix (size 5) in uniprot entity NLRP3_HUMAN there are 6 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 the NLRP3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.1417 (below the threshold of 3.09). Trascript score misZ: 3.5037 (above the threshold of 3.09). GenCC associations: The gene is linked to familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 1-247424662-A-C is Pathogenic according to our data. Variant chr1-247424662-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424662-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.1213A>C	p.Thr405Pro	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.1213A>C	p.Thr405Pro	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cryopyrin associated periodic syndrome Pathogenic:1

Nov 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 97916). This variant is also known as c.1213A>C, p.Thr405Pro, and T405P. This missense change has been observed in individual(s) with NLRP3-related conditions (PMID: 14630794, 21058222, 22566169, 33020839). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 407 of the NLRP3 protein (p.Thr407Pro). -

not provided Pathogenic:1

Aug 28, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The T407P variant, referred to as T405P using alternate nomenclature, has been published previously in association with CINCA syndrome and CAPS (Neven et al., 2004; Lainka et al., 2010; Jesus et al., 2012). The variant is not observed in large population cohorts (Lek et al., 2016). T407P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The variant is located within the NACHT domain, which is a major locus of CAPS-associated pathogenic variants (Masters et al., 2009). We consider this variant to be likely pathogenic. -

Familial cold autoinflammatory syndrome 1 Other:1

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D;D;.;.;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D;.;T;D;.;D;T;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;.;.;D
Polyphen		0.97	D;P;P;D;D;.;.;D
Vest4		0.56
MutPred		0.70		Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);Loss of stability (P = 0.2172);
MVP		0.98
MPC		1.4
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.74
gMVP		0.96

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: rs180177445; hg19: chr1-247587964;