1-247438293-T-C

Variant names:

• chr1-247438293-T-C
• rs12239046
• NM_001243133.2:c.2663+2153T>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+2153T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 151,378 control chromosomes in the GnomAD database, including 25,614 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 0.58 (25614 hom., cov: 29)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 50 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.2663+2153T>C		intron_variant	Intron 7 of 9	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.2663+2153T>C		intron_variant	Intron 7 of 9	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87369 AN: 151260 Hom.: 25588 Cov.: 29

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.578 AC: 87438 AN: 151378 Hom.: 25614 Cov.: 29 AF XY: 0.577 AC XY: 42656 AN XY: 73882

African (AFR) AF: 0.485 AC: 19991 AN: 41184

American (AMR) AF: 0.601 AC: 9137 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1656 AN: 3462

East Asian (EAS) AF: 0.606 AC: 3111 AN: 5132

South Asian (SAS) AF: 0.590 AC: 2843 AN: 4816

European-Finnish (FIN) AF: 0.614 AC: 6341 AN: 10328

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42395 AN: 67944

Other (OTH) AF: 0.573 AC: 1205 AN: 2102

Alfa AF: 0.608 Hom.: 84527

Bravo AF: 0.574

Asia WGS AF: 0.620 AC: 2153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.2
DANN	Benign	0.77
PhyloP100		1.3
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: rs12239046; hg19: chr1-247601595;