1-247421341-G-C

Variant names:

• chr1-247421341-G-C
• rs10754555
• NM_001243133.2:c.278-1889G>C

Variant summary

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

The NM_001243133.2(NLRP3):​c.278-1889G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 151,816 control chromosomes in the GnomAD database, including 25,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: 𝑓 0.58 (25408 hom., cov: 30)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: -1.24
• Publications: 20 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]

NLRP3 Gene-Disease associations (from GenCC):

• CINCA syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cryopyrin-associated periodic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• familial cold autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• familial cold autoinflammatory syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Muckle-Wells syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• keratitis fugax hereditaria

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.278-1889G>C		intron_variant	Intron 2 of 9	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.278-1889G>C		intron_variant	Intron 2 of 9	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87379 AN: 151698 Hom.: 25395 Cov.: 30

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.593

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

GnomAD4 genome AF: 0.576 AC: 87436 AN: 151816 Hom.: 25408 Cov.: 30 AF XY: 0.578 AC XY: 42856 AN XY: 74200

African (AFR) AF: 0.489 AC: 20214 AN: 41356

American (AMR) AF: 0.598 AC: 9125 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2127 AN: 3468

East Asian (EAS) AF: 0.624 AC: 3203 AN: 5136

South Asian (SAS) AF: 0.578 AC: 2780 AN: 4808

European-Finnish (FIN) AF: 0.605 AC: 6386 AN: 10554

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41538 AN: 67918

Other (OTH) AF: 0.592 AC: 1252 AN: 2114

Alfa AF: 0.585 Hom.: 3258

Bravo AF: 0.576

Asia WGS AF: 0.584 AC: 2033 AN: 3478

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Long COVID-19 Pathogenic:1

-

DECIPHERD-UDD, Universidad del Desarrollo

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.40
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10754555; hg19: chr1-247584643;