1-247425556-C-A

Variant names:

• chr1-247425556-C-A
• rs35829419
• NM_001243133.2:c.2107C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The NM_001243133.2(NLRP3):​c.2107C>A​(p.Gln703Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,611,524 control chromosomes in the GnomAD database, including 1,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q703H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (126 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1610 hom.)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: -0.197
• Publications: 296 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.

• PP2: Missense variant in the NLRP3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.1417 (below the threshold of 3.09). Trascript score misZ: 3.5037 (above the threshold of 3.09). GenCC associations: The gene is linked to CINCA syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome, cryopyrin-associated periodic syndrome, keratitis fugax hereditaria.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027211607).
• BP6: Variant 1-247425556-C-A is Benign according to our data. Variant chr1-247425556-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259561.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.2107C>A	p.Gln703Lys	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.2107C>A	p.Gln703Lys	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4990 AN: 152126 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00980

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0391 AC: 9757 AN: 249326 AF XY: 0.0412

Gnomad AFR exome AF: 0.00942

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0654

Gnomad EAS exome AF: 0.00180

Gnomad FIN exome AF: 0.0484

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0444 AC: 64760 AN: 1459280 Hom.: 1610 Cov.: 37 AF XY: 0.0444 AC XY: 32258 AN XY: 726112

African (AFR) AF: 0.00929 AC: 311 AN: 33474

American (AMR) AF: 0.0195 AC: 874 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 1693 AN: 26136

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39698

South Asian (SAS) AF: 0.0374 AC: 3224 AN: 86256

European-Finnish (FIN) AF: 0.0485 AC: 2470 AN: 50946

Middle Eastern (MID) AF: 0.0567 AC: 323 AN: 5700

European-Non Finnish (NFE) AF: 0.0480 AC: 53337 AN: 1111976

Other (OTH) AF: 0.0407 AC: 2455 AN: 60372

GnomAD4 genome AF: 0.0328 AC: 4994 AN: 152244 Hom.: 126 Cov.: 32 AF XY: 0.0325 AC XY: 2417 AN XY: 74424

African (AFR) AF: 0.00987 AC: 410 AN: 41556

American (AMR) AF: 0.0235 AC: 360 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 235 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5176

South Asian (SAS) AF: 0.0357 AC: 172 AN: 4822

European-Finnish (FIN) AF: 0.0475 AC: 504 AN: 10600

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3167 AN: 68010

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0352 Hom.: 84

Bravo AF: 0.0303

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0477 AC: 184

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.0467 AC: 402

ExAC AF: 0.0408 AC: 4957

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0510

EpiControl AF: 0.0514

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Jan 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32477355, 26178285, 32199921, 22843550, 30245029, 29148409, 28638818, 28692792, 29977033, 29265930, 30140708, 29610014, 27576327, 29770580, 23215645, 29850521, 29230505, 22128899, 17509468, 22529966, 28028683, 26020059, 27036377, 27943647, 26848126, 27884173, 22403613, 22995991, 20182451, 25596455, 22935299, 18311798, 21245836, 19319132, 20981092, 29097263, 29500522, 30447690, 30536174) -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, BS1, BP4 -

not specified Benign:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln705Lys variant in NLRP3 is classified as benign because it has been identified in 3.8% (10781/280716) of total chromosomes, including 266 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been reported in association with autoimmune or inflammatory conditions, several studies have shown equal frequency in cases and ethnically matched controls (Jenko 2016, Lidar 2017, Naselli 2016, Yang 2017). ACMG/AMP criteria: BA1. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cryopyrin associated periodic syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis Benign:1

Sep 02, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial amyloid nephropathy with urticaria AND deafness Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autoinflammatory syndrome Benign:1

Feb 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chronic infantile neurological, cutaneous and articular syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.56
DANN	Benign	0.26
DEOGEN2	Benign	0.17	.;T;T;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.69	T;.;T;T;.;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
PhyloP100		-0.20
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.20	N;N;N;N;N;.;.;N
REVEL	Benign	0.16
Sift	Benign	0.23	T;T;T;T;T;.;.;T
Sift4G	Benign	0.58	T;T;T;T;T;.;.;T
Polyphen		0.14	B;B;B;B;B;.;.;B
Vest4		0.10
MPC		0.59
ClinPred		0.0028	T
GERP RS		-0.98
Varity_R		0.096
gMVP		0.37
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35829419; hg19: chr1-247588858; COSMIC: COSV60224157;