rs121908146

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 1.42

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 7 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 [Likely_pathogenic]. Clinvar id is 97925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.

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 rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.1316C>T	p.Ala439Val	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.1316C>T	p.Ala439Val	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460208

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726464

show subpopulations

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Aug 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_very_strong, PP4, PM2, PM6, PS3_moderate, PS4 -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NLRP3: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PM6:Supporting -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 23, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome 1

Pathogenic:2Other:1

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 26, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as A439V or C1316T. ClinVar contains an entry for this variant (Variation ID: 4370). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic. -

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

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome

Pathogenic:1

Jan 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;D;D;.;.;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.079

LIST_S2

Uncertain

0.94

D;.;D;D;.;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.61

PrimateAI

Benign

0.40

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over