rs121908146

chr1-247424765-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001243133.2(NLRP3):c.1316C>T(p.Ala439Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A439P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 1.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001243133.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-247424764-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97925.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, NLRP3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 1-247424765-C-T is Pathogenic according to our data. Variant chr1-247424765-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424765-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2	c.1316C>T	p.Ala439Val	missense_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8	c.1316C>T	p.Ala439Val	missense_variant	4/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460208 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 726464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	Published functional studies demonstrate that individuals with A441V have increased secretion of inflammatory cytokines, which correlates with disease severity (Rieber et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26115477, 22377911, 25596455, 26245507, 11687797, 26931528, 27134254, 28956000, 15801036, 31057541, 30568124, 31777803, 27535533, 19302049) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 23, 2022	The NLRP3 c.1322C>T; p.Ala441Val variant (rs121908146), also known as Ala439Val, is published in the medical literature in several individuals and families with various autoinflammatory syndromes (Aoyama 2012, Hentgen 2005, Hoffman 2001, Houx 2015, Parker 2016) and is described as one of the more common pathogenic variants (Cuisset 2010). The variant is described as occurring de novo in at least one family (Hoffman 2001) and also has been shown to segregate with disease (Hoffman 2001, Hentgen 2005). The variant is reported in ClinVar (Variation ID: 4370), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 441 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.481). Considering available information, this variant is classified as pathogenic. References: Aoyama K et al. Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature. Acta Derm Venereol. 2012 Jul;92(4):395-8. PMID: 22377911. Cuisset L et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011 Mar;70(3):495-9. PMID: 21109514. Hentgen V et al. Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol. 2005 Apr;32(4):747-51. PMID: 15801036. PMID: 11687797. Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5. PMID: 11687797. Houx L et al. Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. Arthritis Rheumatol. 2015 Nov;67(11):3027-36. PMID: 26245507. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51. PMID: 26931528. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial cold autoinflammatory syndrome 1 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 26, 2023	The NLRP3 c.1316C>T variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PP1_Strong) The NLRP3 c.1316C>T variant (also known as p.Ala441Val) is a single nucleotide change in exon 3/9 of the NLRP3 gene, which is predicted to change the amino acid alanine at position 439 in the protein to valine. The variant has been reported in probands with a clinical presentation of Familial Cold Autoinflammatory Syndrome (PS4_Moderate). This variant is absent from population databases (PM2). Segregation with disease is noted within 2 large families, with 19 mutation positive individuals. (PP1_strong) (PubMed: 11687797, 27134254). The variant has been reported in dbSNP (rs121908146) and in the HGMD database: CM013248. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 4370). -

Cryopyrin associated periodic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NLRP3 protein function. ClinVar contains an entry for this variant (Variation ID: 4370). This variant is also known as A439V or C1316T. This missense change has been observed in individuals with NLRP3-related disease (PMID: 11687797, 15801036, 25596455, 26245507, 26931528, 27134254). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the NLRP3 protein (p.Ala441Val). -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.079	N
LIST_S2	Uncertain	0.94	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	5.1e-8	A;A;A;A;A;A
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;.;.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.011	D;D;D;D;D;.;.;D
Polyphen		0.93	P;D;D;D;P;.;.;B
Vest4		0.81
MutPred		0.53		Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);Gain of methylation at K437 (P = 0.0993);
MVP		1.0
MPC		1.2
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.43
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908146; hg19: chr1-247588067; COSMIC: COSV100276461;