rs10399826

Variant names:

• chr1-247372233-A-G
• rs10399826
• ENST00000697408.2:c.-243-1774A>G

Variant summary

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

The ENST00000697408.2(NLRP3):​c.-243-1774A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 151,526 control chromosomes in the GnomAD database, including 5,555 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 0.23 (5555 hom., cov: 32)
• Consequence: NLRP3 ENST00000697408.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.615
• Publications: 3 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]

ZNF496-DT (HGNC:55991): (ZNF496 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 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
	ZNF496-DT	NR_168396.1		n.429-1774A>G		intron	N/A
	ZNF496-DT	NR_168397.1		n.366-1774A>G		intron	N/A
	ZNF496-DT	NR_168399.1		n.1194-1774A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000697408.2		c.-243-1774A>G		intron	N/A	ENSP00000520480.1
	ZNF496-DT	ENST00000697393.1		n.1012-1774A>G		intron	N/A
	ZNF496-DT	ENST00000697394.1		n.100-1774A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34637 AN: 151436 Hom.: 5532 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.00581

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.209

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

GnomAD4 genome AF: 0.229 AC: 34709 AN: 151526 Hom.: 5555 Cov.: 32 AF XY: 0.221 AC XY: 16331 AN XY: 73976

African (AFR) AF: 0.452 AC: 18704 AN: 41336

American (AMR) AF: 0.145 AC: 2200 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 522 AN: 3470

East Asian (EAS) AF: 0.00563 AC: 29 AN: 5150

South Asian (SAS) AF: 0.128 AC: 615 AN: 4800

European-Finnish (FIN) AF: 0.0923 AC: 955 AN: 10346

Middle Eastern (MID) AF: 0.191 AC: 55 AN: 288

European-Non Finnish (NFE) AF: 0.162 AC: 11008 AN: 67904

Other (OTH) AF: 0.208 AC: 437 AN: 2100

Alfa AF: 0.178 Hom.: 4883

Bravo AF: 0.244

Asia WGS AF: 0.103 AC: 361 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.20
PhyloP100		-0.61

Splicing

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

Other links and lift over

dbSNP: rs10399826; hg19: chr1-247535535;