rs3738448

Variant names:

• chr1-247416133-G-T
• rs3738448
• ENST00000697408.2:c.-106-2096G>T

Variant summary

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

The ENST00000697408.2(NLRP3):​c.-106-2096G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 152,484 control chromosomes in the GnomAD database, including 277 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 0.049 (277 hom., cov: 32)
  • Exomes 𝑓: 0.057 (0 hom.)
• Consequence: NLRP3 ENST00000697408.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.360
• Publications: 10 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 = 0.14 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000697408.2. 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.-809G>T		upstream_gene	N/A	NP_001230062.1
	NLRP3	NM_004895.5		c.-803G>T		upstream_gene	N/A	NP_004886.3
	NLRP3	NM_001079821.3		c.-167G>T		upstream_gene	N/A	NP_001073289.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000697408.2		c.-106-2096G>T		intron	N/A	ENSP00000520480.1
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.-809G>T		upstream_gene	N/A	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.-167G>T		upstream_gene	N/A	ENSP00000375704.4

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7425 AN: 152156 Hom.: 277 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0701

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0525

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0527

Gnomad OTH AF: 0.0536

GnomAD4 exome AF: 0.0571 AC: 12 AN: 210 Hom.: 0 Cov.: 0 AF XY: 0.0725 AC XY: 10 AN XY: 138

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0634 AC: 9 AN: 142

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0208 AC: 1 AN: 48

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.0488 AC: 7424 AN: 152274 Hom.: 277 Cov.: 32 AF XY: 0.0516 AC XY: 3842 AN XY: 74466

African (AFR) AF: 0.0114 AC: 474 AN: 41556

American (AMR) AF: 0.0691 AC: 1057 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 243 AN: 3468

East Asian (EAS) AF: 0.148 AC: 768 AN: 5174

South Asian (SAS) AF: 0.0525 AC: 253 AN: 4818

European-Finnish (FIN) AF: 0.0801 AC: 850 AN: 10612

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0527 AC: 3586 AN: 68032

Other (OTH) AF: 0.0549 AC: 116 AN: 2112

Alfa AF: 0.0510 Hom.: 376

Bravo AF: 0.0472

Asia WGS AF: 0.0800 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.77
PhyloP100		0.36
PromoterAI		-0.12	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3738448; hg19: chr1-247579435;