rs10159239

Positions:

• chr1-247443750-G-A
• chr1-247443750-G-C

Variant summary

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

The NM_001243133.2(NLRP3):​c.2664-222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 151,864 control chromosomes in the GnomAD database, including 24,896 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 0.57 (24896 hom., cov: 31)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.908

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]

LOC124904575 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.2664-222G>A		intron_variant		ENST00000336119.8	NP_001230062.1
LOC124904575	XR_007067005.1	n.145-4217C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.2664-222G>A		intron_variant		1	NM_001243133.2	ENSP00000337383	P1

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86228 AN: 151746 Hom.: 24863 Cov.: 31

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.568 AC: 86322 AN: 151864 Hom.: 24896 Cov.: 31 AF XY: 0.570 AC XY: 42266 AN XY: 74210

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.590

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.526

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.552

Alfa AF: 0.543 Hom.: 45573

Bravo AF: 0.574

Asia WGS AF: 0.611 AC: 2125 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs10159239; hg19: chr1-247607052;