NM_001243133.2:c.780A>G

Variant names:

• chr1-247424229-A-G
• rs4925543
• NM_001243133.2:c.780A>G

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.780A>G​(p.Arg260Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 1,614,012 control chromosomes in the GnomAD database, including 727,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65767 hom., cov: 30)
  • Exomes 𝑓: 0.95 (661478 hom.)
• Consequence: NLRP3 NM_001243133.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0360
• Publications: 28 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=-0.61).
• BP6: Variant 1-247424229-A-G is Benign according to our data. Variant chr1-247424229-A-G is described in ClinVar as Benign. ClinVar VariationId is 403243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.036 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.780A>G	p.Arg260Arg	synonymous	Exon 4 of 10	NP_001230062.1
	NLRP3	NM_004895.5		c.786A>G	p.Arg262Arg	synonymous	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.780A>G	p.Arg260Arg	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.780A>G	p.Arg260Arg	synonymous	Exon 4 of 10	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.780A>G	p.Arg260Arg	synonymous	Exon 5 of 11	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.780A>G	p.Arg260Arg	synonymous	Exon 3 of 8	ENSP00000355452.3

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141148 AN: 152016 Hom.: 65724 Cov.: 30

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.960

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.955

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.958

Gnomad OTH AF: 0.929

GnomAD2 exomes AF: 0.946 AC: 237877 AN: 251380 AF XY: 0.944

Gnomad AFR exome AF: 0.848

Gnomad AMR exome AF: 0.971

Gnomad ASJ exome AF: 0.971

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.950

Gnomad NFE exome AF: 0.958

Gnomad OTH exome AF: 0.954

GnomAD4 exome AF: 0.951 AC: 1390021 AN: 1461878 Hom.: 661478 Cov.: 69 AF XY: 0.949 AC XY: 690079 AN XY: 727238

African (AFR) AF: 0.857 AC: 28689 AN: 33480

American (AMR) AF: 0.968 AC: 43300 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 25379 AN: 26136

East Asian (EAS) AF: 0.999 AC: 39679 AN: 39700

South Asian (SAS) AF: 0.878 AC: 75722 AN: 86258

European-Finnish (FIN) AF: 0.952 AC: 50859 AN: 53414

Middle Eastern (MID) AF: 0.939 AC: 5419 AN: 5768

European-Non Finnish (NFE) AF: 0.956 AC: 1063596 AN: 1112004

Other (OTH) AF: 0.950 AC: 57378 AN: 60394

GnomAD4 genome AF: 0.928 AC: 141248 AN: 152134 Hom.: 65767 Cov.: 30 AF XY: 0.928 AC XY: 69027 AN XY: 74354

African (AFR) AF: 0.855 AC: 35474 AN: 41484

American (AMR) AF: 0.952 AC: 14563 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 3372 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5137 AN: 5150

South Asian (SAS) AF: 0.890 AC: 4281 AN: 4810

European-Finnish (FIN) AF: 0.955 AC: 10109 AN: 10590

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.958 AC: 65190 AN: 68022

Other (OTH) AF: 0.929 AC: 1963 AN: 2112

Alfa AF: 0.949 Hom.: 103748

Bravo AF: 0.927

Asia WGS AF: 0.947 AC: 3296 AN: 3478

EpiCase AF: 0.958

EpiControl AF: 0.955

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cold autoinflammatory syndrome 1 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Keratitis fugax hereditaria Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Chronic infantile neurological, cutaneous and articular syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.1
DANN	Benign	0.47
PhyloP100		-0.036
Mutation Taster		=99/1	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: rs4925543; hg19: chr1-247587531; COSMIC: COSV108145782;