1-247424106-C-T

Variant names:

• chr1-247424106-C-T
• rs7525979
• NM_001243133.2:c.657C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001243133.2(NLRP3):​c.657C>T​(p.Thr219Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,613,902 control chromosomes in the GnomAD database, including 5,177 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. T219T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1291 hom., cov: 31)
  • Exomes 𝑓: 0.065 (3886 hom.)
• Consequence: NLRP3 NM_001243133.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -10.6
• Publications: 34 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-247424106-C-T is Benign according to our data. Variant chr1-247424106-C-T is described in ClinVar as Benign. ClinVar VariationId is 259562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-10.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

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.657C>T	p.Thr219Thr	synonymous	Exon 4 of 10	NP_001230062.1
	NLRP3	NM_004895.5		c.663C>T	p.Thr221Thr	synonymous	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.657C>T	p.Thr219Thr	synonymous	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.657C>T	p.Thr219Thr	synonymous	Exon 4 of 10	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.657C>T	p.Thr219Thr	synonymous	Exon 5 of 11	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.657C>T	p.Thr219Thr	synonymous	Exon 3 of 8	ENSP00000355452.3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16651 AN: 151920 Hom.: 1290 Cov.: 31

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0920

Gnomad ASJ AF: 0.0758

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0579

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0802 AC: 20156 AN: 251268 AF XY: 0.0755

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0847

Gnomad ASJ exome AF: 0.0805

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.0870

Gnomad NFE exome AF: 0.0573

Gnomad OTH exome AF: 0.0779

GnomAD4 exome AF: 0.0647 AC: 94567 AN: 1461864 Hom.: 3886 Cov.: 32 AF XY: 0.0639 AC XY: 46440 AN XY: 727232

African (AFR) AF: 0.225 AC: 7544 AN: 33480

American (AMR) AF: 0.0853 AC: 3817 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 2093 AN: 26136

East Asian (EAS) AF: 0.149 AC: 5925 AN: 39680

South Asian (SAS) AF: 0.0476 AC: 4106 AN: 86258

European-Finnish (FIN) AF: 0.0839 AC: 4480 AN: 53420

Middle Eastern (MID) AF: 0.0872 AC: 503 AN: 5768

European-Non Finnish (NFE) AF: 0.0553 AC: 61469 AN: 1112002

Other (OTH) AF: 0.0767 AC: 4630 AN: 60396

GnomAD4 genome AF: 0.110 AC: 16670 AN: 152038 Hom.: 1291 Cov.: 31 AF XY: 0.111 AC XY: 8252 AN XY: 74338

African (AFR) AF: 0.213 AC: 8815 AN: 41432

American (AMR) AF: 0.0917 AC: 1403 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 263 AN: 3470

East Asian (EAS) AF: 0.147 AC: 756 AN: 5158

South Asian (SAS) AF: 0.0529 AC: 254 AN: 4806

European-Finnish (FIN) AF: 0.0880 AC: 931 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0579 AC: 3936 AN: 67978

Other (OTH) AF: 0.104 AC: 220 AN: 2114

Alfa AF: 0.0736 Hom.: 2397

Bravo AF: 0.116

Asia WGS AF: 0.0910 AC: 315 AN: 3478

EpiCase AF: 0.0612

EpiControl AF: 0.0606

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr221Thr in exon 5 of the NLPR3 gene: This variant is not expected to have cl inical significance because it does not alter an amino acid residue and it has b een identified in 8% (23018/276946) of the total chromosomes by the the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7525979).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30246732, 30131971)

Familial cold autoinflammatory syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial amyloid nephropathy with urticaria AND deafness Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Chronic infantile neurological, cutaneous and articular syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.026
DANN	Benign	0.57
PhyloP100		-11
Mutation Taster		=100/0	polymorphism (auto)

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: rs7525979; hg19: chr1-247587408; COSMIC: COSV60221249;