rs34298354

chr1-247424751-C-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.1302C>T(p.Ser434=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,382 control chromosomes in the GnomAD database, including 11,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (767 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10728 hom.)
• Consequence: NLRP3 NM_001243133.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -1.26

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=-0.53).
• BP6: Variant 1-247424751-C-T is Benign according to our data. Variant chr1-247424751-C-T is described in ClinVar as [Benign]. Clinvar id is 259560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424751-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2	c.1302C>T	p.Ser434=	synonymous_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8	c.1302C>T	p.Ser434=	synonymous_variant	4/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13466 AN: 152126 Hom.: 769 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0834

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0961

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.0985

GnomAD3 exomes AF: 0.101 AC: 25286 AN: 250564 Hom.: 1487 AF XY: 0.106 AC XY: 14406 AN XY: 135486

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.0588

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0685

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.117 AC: 171353 AN: 1461138 Hom.: 10728 Cov.: 43 AF XY: 0.119 AC XY: 86180 AN XY: 726882

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0614

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0967

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0884 AC: 13455 AN: 152244 Hom.: 767 Cov.: 32 AF XY: 0.0873 AC XY: 6495 AN XY: 74424

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0833

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0768

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0961

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.107 Hom.: 470

Bravo AF: 0.0830

Asia WGS AF: 0.0830 AC: 290 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.130

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 22, 2017	p.Ser436Ser in exon 5 of NLRP3: This variant is not expected to have clinical si gnificance because it has been identified in 12.65% (16000/126506) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org/; dbSNP rs34298354). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 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	clinical testing	GeneDx	Mar 03, 2015	- -

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 12, 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 12, 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 12, 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

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	-0.53
Cadd	Benign	4.3
Dann	Benign	0.55

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: rs34298354; hg19: chr1-247588053; COSMIC: COSV60220717;