1-247436999-A-C

Variant names:

• chr1-247436999-A-C
• rs1539019
• NM_001243133.2:c.2663+859A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243133.2(NLRP3):​c.2663+859A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 152,106 control chromosomes in the GnomAD database, including 30,036 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (30036 hom., cov: 32)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.223
• Publications: 46 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243133.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	NM_001243133.2	MANE Select	c.2663+859A>C		intron	N/A	NP_001230062.1
	NLRP3	NM_004895.5		c.2669+859A>C		intron	N/A	NP_004886.3
	NLRP3	NM_001079821.3		c.2663+859A>C		intron	N/A	NP_001073289.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.2663+859A>C		intron	N/A	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.2663+859A>C		intron	N/A	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.2492+2726A>C		intron	N/A	ENSP00000355452.3

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95176 AN: 151988 Hom.: 29993 Cov.: 32

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.608

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

GnomAD4 genome AF: 0.626 AC: 95282 AN: 152106 Hom.: 30036 Cov.: 32 AF XY: 0.625 AC XY: 46502 AN XY: 74354

African (AFR) AF: 0.655 AC: 27161 AN: 41494

American (AMR) AF: 0.700 AC: 10704 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1573 AN: 3466

East Asian (EAS) AF: 0.609 AC: 3149 AN: 5172

South Asian (SAS) AF: 0.581 AC: 2803 AN: 4826

European-Finnish (FIN) AF: 0.584 AC: 6170 AN: 10572

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.614 AC: 41702 AN: 67970

Other (OTH) AF: 0.610 AC: 1291 AN: 2116

Alfa AF: 0.615 Hom.: 102736

Bravo AF: 0.637

Asia WGS AF: 0.628 AC: 2183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		-0.22
Mutation Taster		=100/0	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: rs1539019; hg19: chr1-247600301;