rs4612666

Variant names:

• chr1-247435768-T-C
• rs4612666
• NM_001243133.2:c.2493-202T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001243133.2(NLRP3):​c.2493-202T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 152,056 control chromosomes in the GnomAD database, including 33,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.65 (33309 hom., cov: 32)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.401
• Publications: 118 publications found

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 Gene-Disease associations (from GenCC):

• CINCA syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cryopyrin-associated periodic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• familial cold autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• familial cold autoinflammatory syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Muckle-Wells syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• keratitis fugax hereditaria

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-247435768-T-C is Benign according to our data. Variant chr1-247435768-T-C is described in ClinVar as Benign. ClinVar VariationId is 1169053.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.2493-202T>C		intron_variant	Intron 6 of 9	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.2493-202T>C		intron_variant	Intron 6 of 9	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98603 AN: 151938 Hom.: 33319 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.689

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.649 AC: 98624 AN: 152056 Hom.: 33309 Cov.: 32 AF XY: 0.648 AC XY: 48139 AN XY: 74338

African (AFR) AF: 0.457 AC: 18921 AN: 41438

American (AMR) AF: 0.655 AC: 10008 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2725 AN: 3468

East Asian (EAS) AF: 0.548 AC: 2837 AN: 5180

South Asian (SAS) AF: 0.655 AC: 3156 AN: 4820

European-Finnish (FIN) AF: 0.740 AC: 7825 AN: 10574

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.749 AC: 50921 AN: 67992

Other (OTH) AF: 0.686 AC: 1449 AN: 2112

Alfa AF: 0.711 Hom.: 106480

Bravo AF: 0.634

Asia WGS AF: 0.615 AC: 2144 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryopyrin associated periodic syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.76
PhyloP100		0.40
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4612666; hg19: chr1-247599070; COSMIC: COSV60223405;