rs12048215

Variant names:

• chr1-247421289-A-G
• rs12048215
• NM_001243133.2:c.278-1941A>G

Variant summary

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

The NM_001243133.2(NLRP3):​c.278-1941A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 151,924 control chromosomes in the GnomAD database, including 1,172 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 0.11 (1172 hom., cov: 32)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0880
• Publications: 11 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.278-1941A>G		intron_variant	Intron 2 of 9	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.278-1941A>G		intron_variant	Intron 2 of 9	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17317 AN: 151806 Hom.: 1162 Cov.: 32

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.0839

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.103

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

GnomAD4 genome AF: 0.114 AC: 17344 AN: 151924 Hom.: 1172 Cov.: 32 AF XY: 0.116 AC XY: 8619 AN XY: 74250

African (AFR) AF: 0.0586 AC: 2428 AN: 41438

American (AMR) AF: 0.168 AC: 2558 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3468

East Asian (EAS) AF: 0.296 AC: 1515 AN: 5122

South Asian (SAS) AF: 0.165 AC: 794 AN: 4812

European-Finnish (FIN) AF: 0.132 AC: 1395 AN: 10560

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7872 AN: 67954

Other (OTH) AF: 0.107 AC: 226 AN: 2108

Alfa AF: 0.120 Hom.: 876

Bravo AF: 0.114

Asia WGS AF: 0.244 AC: 848 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.84
PhyloP100		-0.088
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: rs12048215; hg19: chr1-247584591;