rs117287351

Variant names:

• chr1-247419008-G-A
• rs117287351
• NM_001243133.2:c.208G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-247419008-G-A
• chr1-247419008-G-C
• chr1-247419008-G-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.208G>A​(p.Val70Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,613,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. V70L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.357
• Publications: 25 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=0.004709512).
• BP6: Variant 1-247419008-G-A is Benign according to our data. Variant chr1-247419008-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245593.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00044 (67/152306) while in subpopulation EAS AF = 0.01 (52/5178). AF 95% confidence interval is 0.00787. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.208G>A	p.Val70Met	missense_variant	Exon 2 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.208G>A	p.Val70Met	missense_variant	Exon 2 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000759 AC: 190 AN: 250408 AF XY: 0.000717

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00897

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000421 AC: 616 AN: 1461662 Hom.: 4 Cov.: 31 AF XY: 0.000396 AC XY: 288 AN XY: 727106

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26136

East Asian (EAS) AF: 0.0110 AC: 437 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1112000

Other (OTH) AF: 0.000497 AC: 30 AN: 60394

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74478

African (AFR) AF: 0.0000963 AC: 4 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000402 Hom.: 1

Bravo AF: 0.000514

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jun 08, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NLRP3 c.214G>A;p.Val72Met variant has been listed in the medical literature in at least two individuals with autoinflammatory disease (Nakayama 2017). The variant is listed in the ClinVar database (Variation ID: 245593) and in the dbSNP variant database (rs117287351) with an allele frequency of up to 0.9 percent (171/18868 alleles) in East Asians in the Genome Aggregation Database. The amino acid at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, the clinical significance cannot be determined with certainty. If this variant is later determined to be pathogenic, this individual is predicted to be affected with autosomal dominant CINCA syndrome, Familial cold-induced inflammatory syndrome, or Muckle-Wells syndrome (OMIM#606416). References: Nakayama M et al. Accurate clinical genetic testing for autoinflammatory diseases using the next-generation sequencing platform MiSeq. Biochem Biophys Rep 2017 9:146-152. -

Feb 02, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28028683, 23633568, 31172726, 28956000, 31664448, 33329557, 32115236) -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NLRP3: BP4, BS1 -

not specified Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val72Met in exon 1 of NLRP3: This variant is not expected to have clinical significance because it has been identified in 0.81% (70/8600) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs117287351). -

Familial cold autoinflammatory syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cryopyrin associated periodic syndrome Benign:1

Jan 23, 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autoinflammatory syndrome Benign:1

Mar 17, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely 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: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;T;.;.;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.73	T;.;T;T;.;T;T;T
MetaRNN	Benign	0.0047	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
PhyloP100		-0.36
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.030	N;N;N;N;N;.;.;N
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.012	D;D;D;D;D;.;.;D
Polyphen		0.99	D;D;D;D;D;.;.;D
Vest4		0.12
MVP		0.87
MPC		0.61
ClinPred		0.070	T
GERP RS		-4.6
PromoterAI		-0.055	Neutral
Varity_R		0.19
gMVP		0.60
Mutation Taster		=1/99	disease causing

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: rs117287351; hg19: chr1-247582310; COSMIC: COSV60222451;