1-247416133-G-T

Position:

• chr1-247416133-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_047443535.1(NLRP3):​c.-743+37G>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 XM_047443535.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.360

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2			upstream_gene_variant		ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8			upstream_gene_variant		1	NM_001243133.2	P1
NLRP3	ENST00000391827.3			upstream_gene_variant		1
NLRP3	ENST00000391828.8			upstream_gene_variant		1		P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.0634

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.125

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

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0691

Gnomad4 ASJ AF: 0.0701

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.0525

Gnomad4 FIN AF: 0.0801

Gnomad4 NFE AF: 0.0527

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0521 Hom.: 303

Bravo AF: 0.0472

Asia WGS AF: 0.0800 AC: 276 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	4.0
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3738448; hg19: chr1-247579435;