rs180177438

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate

The NM_001243133.2(NLRP3):c.1709A>G(p.Tyr570Cys) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y570F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 4.17

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]

NLRP3 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-247425158-A-T is described in Lovd as [Likely_pathogenic].

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, 0.808

PP5

Variant 1-247425158-A-G is Pathogenic according to our data. Variant chr1-247425158-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 97946.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-247425158-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.1709A>G	p.Tyr570Cys	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.1709A>G	p.Tyr570Cys	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (Nakamura et al., 2009; Tanaka et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.Y570C; This variant is associated with the following publications: (PMID: 33329557, 32810141, 23703389, 30288079, 20007570, 12930324, 19364881, 21702021, 25302486, 22723549, 28916543, 25979514, 33042144, 21832064, 20500518, 12483741, 25988971, 33020839, 35159338, Kim[CaseReport]2018, 16255047, 32181272) -

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

Benign

0.26

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

.;D;D;.;.;.;.;.

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.94

D;.;D;D;.;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.30

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;.;.;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.022

D;D;D;D;D;.;.;D

Sift4G

Uncertain

0.014

D;D;D;D;D;.;.;D

Polyphen

0.57

P;B;B;D;P;.;.;P

Vest4

0.89

MutPred

0.63

Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);Gain of catalytic residue at L573 (P = 0.0197);

MVP

1.0

MPC

1.5

ClinPred

0.99

GERP RS

4.0

Varity_R

0.72

gMVP

0.80

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over