rs3806268

chr1-247424175-G-Achr1-247424175-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001243133.2(NLRP3):c.726G>A(p.Ala242=) 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:15 O:1
• Conservation: PhyloP100: -2.23

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 138528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424175-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2	c.726G>A	p.Ala242=	synonymous_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8	c.726G>A	p.Ala242=	synonymous_variant	4/10	1	NM_001243133.2	P1

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

GnomAD3 exomes AF: 0.503 AC: 126273 AN: 251266 Hom.: 33377 AF XY: 0.518 AC XY: 70311 AN XY: 135808

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 SAS exome AF: 0.544

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

Gnomad4 AFR exome AF: 0.0964

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.574

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.545

Gnomad4 NFE exome AF: 0.564

Gnomad4 OTH exome AF: 0.523

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

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.544

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.536

Gnomad4 NFE AF: 0.561

Gnomad4 OTH AF: 0.445

Alfa AF: 0.522 Hom.: 25016

Bravo AF: 0.398

Asia WGS AF: 0.516 AC: 1796 AN: 3478

EpiCase AF: 0.560

EpiControl AF: 0.557

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	p.Ala244Ala in exon 5 of NLRP3: This variant is not expected to have clinical si gnificance because it has been identified in 49.5% (137182/276910) of chromosome s from several racial/ethnically diverse populations by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org/; dbSNPrs3806268). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

Familial cold autoinflammatory syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial amyloid nephropathy with urticaria AND deafness Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Chronic infantile neurological, cutaneous and articular syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Cryopyrin associated periodic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Keratitis fugax hereditaria Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.21
Dann	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs3806268; hg19: chr1-247587477; COSMIC: COSV60221462;