chr1-247379536-A-G

Variant names:

• chr1-247379536-A-G
• rs11802371
• ENST00000697408.2:c.-107+5393A>G

Variant summary

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

The ENST00000697408.2(NLRP3):​c.-107+5393A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,886 control chromosomes in the GnomAD database, including 17,721 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 0.47 (17721 hom., cov: 33)
• Consequence: NLRP3 ENST00000697408.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0940
• Publications: 1 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000697408.2	c.-107+5393A>G		intron_variant	Intron 3 of 11			ENSP00000520480.1
ZNF496-DT	ENST00000697395.1	n.1181+5393A>G		intron_variant	Intron 3 of 4
ZNF496-DT	ENST00000697397.1	n.581-13605A>G		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71510 AN: 151768 Hom.: 17679 Cov.: 33

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.472 AC: 71621 AN: 151886 Hom.: 17721 Cov.: 33 AF XY: 0.466 AC XY: 34594 AN XY: 74206

African (AFR) AF: 0.640 AC: 26512 AN: 41436

American (AMR) AF: 0.438 AC: 6682 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3466

East Asian (EAS) AF: 0.362 AC: 1874 AN: 5172

South Asian (SAS) AF: 0.419 AC: 2011 AN: 4802

European-Finnish (FIN) AF: 0.343 AC: 3606 AN: 10526

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28628 AN: 67930

Other (OTH) AF: 0.445 AC: 937 AN: 2106

Alfa AF: 0.428 Hom.: 2001

Bravo AF: 0.480

Asia WGS AF: 0.449 AC: 1560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.4
DANN	Benign	0.64
PhyloP100		-0.094

Splicing

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

Other links and lift over

dbSNP: rs11802371; hg19: chr1-247542838;