rs180177438

Positions:

• chr1-247425158-A-G
• chr1-247425158-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_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 Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.17

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 10 ACMG points.

• PM1: In a turn (size 3) in uniprot entity NLRP3_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) 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 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.
• 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/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.1709A>G	p.Tyr570Cys	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.1709A>G	p.Tyr570Cys	missense_variant	4/10	1	NM_001243133.2	ENSP00000337383	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2022

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

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	0.26
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	.;D;D;.;.;.;.;.
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.94	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
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	D
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

Other links and lift over

dbSNP: rs180177438; hg19: chr1-247588460;