rs3806268

Variant names:

• chr1-247424175-G-A
• rs3806268
• NM_001243133.2:c.726G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-247424175-G-A
• chr1-247424175-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001243133.2(NLRP3):​c.726G>A​(p.Ala242Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 1,613,644 control chromosomes in the GnomAD database, including 237,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A242A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.42 (16371 hom., cov: 30)
  • Exomes 𝑓: 0.54 (221580 hom.)
• Consequence: NLRP3 NM_001243133.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -2.23
• Publications: 61 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• cryopyrin-associated periodic syndrome

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-247424175-G-A is Benign according to our data. Variant chr1-247424175-G-A is described in ClinVar as Benign. ClinVar VariationId is 138528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243133.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	NM_001243133.2	MANE Select	c.726G>A	p.Ala242Ala	synonymous	Exon 4 of 10	NP_001230062.1	A0A7I2R3P8
	NLRP3	NM_004895.5		c.732G>A	p.Ala244Ala	synonymous	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.726G>A	p.Ala242Ala	synonymous	Exon 5 of 11	NP_001073289.2	A0A7I2R3P8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.726G>A	p.Ala242Ala	synonymous	Exon 4 of 10	ENSP00000337383.4	A0A7I2R3P8
	NLRP3	ENST00000391828.8	TSL:1	c.726G>A	p.Ala242Ala	synonymous	Exon 5 of 11	ENSP00000375704.4	A0A7I2R3P8
	NLRP3	ENST00000366496.7	TSL:1	c.726G>A	p.Ala242Ala	synonymous	Exon 3 of 8	ENSP00000355452.3	A0A7I2PMC6

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63808 AN: 151734 Hom.: 16379 Cov.: 30

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.446

GnomAD2 exomes AF: 0.503 AC: 126273 AN: 251266 AF XY: 0.518

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.567

Gnomad EAS exome AF: 0.532

Gnomad FIN exome AF: 0.544

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.545 AC: 796478 AN: 1461792 Hom.: 221580 Cov.: 60 AF XY: 0.547 AC XY: 397726 AN XY: 727194

African (AFR) AF: 0.0964 AC: 3229 AN: 33480

American (AMR) AF: 0.409 AC: 18277 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 14891 AN: 26136

East Asian (EAS) AF: 0.574 AC: 22764 AN: 39690

South Asian (SAS) AF: 0.541 AC: 46686 AN: 86252

European-Finnish (FIN) AF: 0.545 AC: 29130 AN: 53412

Middle Eastern (MID) AF: 0.537 AC: 3095 AN: 5768

European-Non Finnish (NFE) AF: 0.564 AC: 626834 AN: 1111940

Other (OTH) AF: 0.523 AC: 31572 AN: 60390

GnomAD4 genome AF: 0.420 AC: 63790 AN: 151852 Hom.: 16371 Cov.: 30 AF XY: 0.423 AC XY: 31355 AN XY: 74192

African (AFR) AF: 0.115 AC: 4775 AN: 41442

American (AMR) AF: 0.410 AC: 6254 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1957 AN: 3462

East Asian (EAS) AF: 0.544 AC: 2790 AN: 5128

South Asian (SAS) AF: 0.552 AC: 2649 AN: 4798

European-Finnish (FIN) AF: 0.536 AC: 5652 AN: 10540

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38090 AN: 67908

Other (OTH) AF: 0.445 AC: 938 AN: 2110

Alfa AF: 0.480 Hom.: 33181

Bravo AF: 0.398

Asia WGS AF: 0.516 AC: 1796 AN: 3478

EpiCase AF: 0.560

EpiControl AF: 0.557

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Chronic infantile neurological, cutaneous and articular syndrome (2)
-	-	2	Familial amyloid nephropathy with urticaria AND deafness (2)
-	-	2	Familial cold autoinflammatory syndrome 1 (2)
-	-	2	not provided (3)
-	-	1	Cryopyrin associated periodic syndrome (1)
-	-	1	Keratitis fugax hereditaria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.21
DANN	Benign	0.33
PhyloP100		-2.2
Mutation Taster		=99/1	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: rs3806268; hg19: chr1-247587477; COSMIC: COSV60221462;