rs3806268

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: -2.23

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.547

AC XY:

397726

AN XY:

727194

show subpopulations

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.:

AF XY:

0.423

AC XY:

31355

AN XY:

74192

show subpopulations

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:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided

Benign:2Other: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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Cryopyrin associated periodic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over