1-247425088-A-T

Variant names:

• chr1-247425088-A-T
• rs139833874
• NM_001243133.2:c.1639A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001243133.2(NLRP3):​c.1639A>T​(p.Ser547Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: -0.852
• Publications: 1 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=0.009019583).
• BP6: Variant 1-247425088-A-T is Benign according to our data. Variant chr1-247425088-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536887.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000854 (130/152258) while in subpopulation AFR AF = 0.00294 (122/41548). AF 95% confidence interval is 0.00251. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 130 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	NM_001243133.2	MANE Select	c.1639A>T	p.Ser547Cys	missense	Exon 4 of 10	NP_001230062.1
	NLRP3	NM_004895.5		c.1645A>T	p.Ser549Cys	missense	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.1639A>T	p.Ser547Cys	missense	Exon 5 of 11	NP_001073289.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.1639A>T	p.Ser547Cys	missense	Exon 4 of 10	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.1639A>T	p.Ser547Cys	missense	Exon 5 of 11	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.1639A>T	p.Ser547Cys	missense	Exon 3 of 8	ENSP00000355452.3

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000282 AC: 71 AN: 251340 AF XY: 0.000213

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461882 Hom.: 0 Cov.: 38 AF XY: 0.0000921 AC XY: 67 AN XY: 727242

African (AFR) AF: 0.00343 AC: 115 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74442

African (AFR) AF: 0.00294 AC: 122 AN: 41548

American (AMR) AF: 0.000458 AC: 7 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000371 AC: 45

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Mar 21, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1

Apr 18, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in two patients with NLRP3-related disorders in the published literature (PMID: 19302049, Brighouse 2018 https://doi.org/10.1093/rheumatology/key273.008); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.S547C; This variant is associated with the following publications: (PMID: 19302049)

Mar 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C1835697:Keratitis fugax hereditaria;C4521680:Hearing loss, autosomal dominant 34, with or without inflammation;C4551895:Familial cold autoinflammatory syndrome 1 Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NLRP3 NM_004895.4 exon 4 p.Ser549Cys (c.1645A>T): This variant has not been reported in the literature and is present in 0.3% (81/24950) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-247588390-A-T). This variant is present in ClinVar (Variation ID:536887). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Hearing loss, autosomal dominant 34, with or without inflammation Uncertain:1

Jun 01, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This NLRP3 variant (rs139833874) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African/African American subpopulation (gnomAD: 81/24950 alleles; 0.3%; no homozygotes). This patient's ethnicity is reported to be African American and Hispanic. This variant has been reported in ClinVar and in two meeting abstracts describing individuals with NLRP3-AID. This missense change affects a residue in the helical 2 (HD2) subdomain of the NLRP3 protein but does not occur in any known hotspot associated with NLRP3-AID. Three bioinformatic tools queried predict that the substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function variants. The serine residue at this position is conserved across primates, but weakly conserved across other vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 4 splicing, although this has not been confirmed experimentally to our knowledge. We consider the clinical significance of this variant to be uncertain at this time. knowledge. Due to insufficient evidence, we consider the clinical significance of c.1639A>T to be uncertain at this time.

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C4551895:Familial cold autoinflammatory syndrome 1 Uncertain:1

Dec 03, 2018

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NLRP3 NM_004895.4 exon 4 p.Ser549Cys (c.1645A>T): This variant has not been reported in the literature and is present in 0.3% (81/24950) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-247588390-A-T). This variant is present in ClinVar (Variation ID:536887). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

not specified Benign:1

Jan 16, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser549Cys variant in NLRP3 is classified as likely benign because it has b een identified in 0.3% (81/24950) of African chromosomes by gnomAD (http://gnoma d.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4.

NLRP3-related disorder Benign:1

Feb 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Cryopyrin associated periodic syndrome Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.23
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	-0.17	T
PhyloP100		-0.85
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.42
Sift	Benign	0.052	T
Sift4G	Benign	0.075	T
Polyphen		0.94	P
Vest4		0.22
MVP		0.99
MPC		0.91
ClinPred		0.022	T
GERP RS		-4.2
Varity_R		0.10
gMVP		0.69
Mutation Taster		=86/14	polymorphism

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: rs139833874; hg19: chr1-247588390; COSMIC: COSV99053258;