NM_001243133.2:c.1306A>G

Variant names:

• chr1-247424755-A-G
• rs180177465
• NM_001243133.2:c.1306A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001243133.2(NLRP3):​c.1306A>G​(p.Thr436Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T436N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 2.43
• Publications: 9 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-247424756-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 97924.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 CINCA syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome, cryopyrin-associated periodic syndrome, keratitis fugax hereditaria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 1-247424755-A-G is Pathogenic according to our data. Variant chr1-247424755-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97921.

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.1306A>G	p.Thr436Ala	missense	Exon 4 of 10	NP_001230062.1
	NLRP3	NM_004895.5		c.1312A>G	p.Thr438Ala	missense	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.1306A>G	p.Thr436Ala	missense	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.1306A>G	p.Thr436Ala	missense	Exon 4 of 10	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.1306A>G	p.Thr436Ala	missense	Exon 5 of 11	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.1306A>G	p.Thr436Ala	missense	Exon 3 of 8	ENSP00000355452.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Dec 19, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The T438A variant has been published previously in association with an NLRP3-associated disorder (Zeft et al., 2007). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. T438A is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the NACHT domain where amino acids with similar properties to Threonine are tolerated across species. The NACHT domain is a known locus for pathogenic variants (Masters et al., 2009), and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, T438A has been reported to impair expression of the NLRP3 protein; however, the authors did not publish their data (Guo et al., 2016). Missense variants in the same residue (T438P/I/N) and in nearby residues (T435I, K437E, A441P/T/V, Y443H) have been reported in the Human Gene Mutation Database in association with NLRP3-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic.

Cryopyrin associated periodic syndrome Uncertain:1

Jan 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cryopyrin-associated periodic syndrome (CAPS) (PMID: 17513575, 27191192 ). This variant is also known as c.1306A>G p.T436A in the literature. ClinVar contains an entry for this variant (Variation ID: 97921). In an experimental study, this missense change resulted in decreased expression of the NLRP3 protein product (PMID: 27692610). The clinical significance of these results is uncertain. Other variants that disrupt the p.Thr438 amino acid residue in NLRP3 have been observed in affected individuals (PMID: 26245507, 14630794, 28501347, 12032915). This suggests that it is a clinically significant residue, and that variants that disrupt this residue may be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces threonine with alanine at codon 438 of the NLRP3 protein (p.Thr438Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine.

Familial cold autoinflammatory syndrome 1 Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
PhyloP100		2.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.89		Gain of phosphorylation at T435 (P = 0.1149)
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.79
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs180177465; hg19: chr1-247588057;