rs2027432

Positions:

• chr1-247415139-A-G
• chr1-247415139-A-T

Variant summary

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

The variant allele was found at a frequency of 0.833 in 152,176 control chromosomes in the GnomAD database, including 52,878 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 0.83 (52878 hom., cov: 31)
• Consequence: intergenic_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182

Genes affected

(HGNC:):

ENSG00000289728 (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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.247415139A>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000289728	ENST00000697408.1	n.343-3090A>G		intron_variant				ENSP00000520480.1

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126641 AN: 152058 Hom.: 52830 Cov.: 31

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.925

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.855

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.822

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

GnomAD4 genome AF: 0.833 AC: 126749 AN: 152176 Hom.: 52878 Cov.: 31 AF XY: 0.833 AC XY: 62001 AN XY: 74408

Gnomad4 AFR AF: 0.838

Gnomad4 AMR AF: 0.856

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.925

Gnomad4 SAS AF: 0.754

Gnomad4 FIN AF: 0.855

Gnomad4 NFE AF: 0.820

Gnomad4 OTH AF: 0.824

Alfa AF: 0.815 Hom.: 65850

Bravo AF: 0.837

Asia WGS AF: 0.853 AC: 2967 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	0.66
DANN	Benign	0.34

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2027432; hg19: chr1-247578441;