NM_001243133.2:c.2062G>A

Variant names:

• chr1-247425511-G-A
• rs104895414
• NM_001243133.2:c.2062G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001243133.2(NLRP3):​c.2062G>A​(p.Glu688Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.487
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.2983538).

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.2062G>A	p.Glu688Lys	missense	Exon 4 of 10	NP_001230062.1
	NLRP3	NM_004895.5		c.2068G>A	p.Glu690Lys	missense	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.2062G>A	p.Glu688Lys	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.2062G>A	p.Glu688Lys	missense	Exon 4 of 10	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.2062G>A	p.Glu688Lys	missense	Exon 5 of 11	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.2062G>A	p.Glu688Lys	missense	Exon 3 of 8	ENSP00000355452.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chronic infantile neurological, cutaneous and articular syndrome Uncertain:1

Oct 18, 2024

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with NLRP3 related disorder (PMID: 16920754). However, the evidence of pathogenicity is insufficient at this time.A different missense change at the same codon (p.Glu688Gln) has been reported to be associated with NLRP3 related disorder (PMID: 32813153). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

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	Benign	0.094
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.56	T
PhyloP100		0.49
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.49
Sift	Benign	0.20	T
Sift4G	Benign	0.30	T
Polyphen		0.13	B
Vest4		0.72
MutPred		0.71		Gain of ubiquitination at E690 (P = 0.0094)
MVP		1.0
MPC		0.68
ClinPred		0.51	D
GERP RS		3.9
Varity_R		0.24
gMVP		0.57
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: rs104895414; hg19: chr1-247588813; COSMIC: COSV60231611;