1-247425425-T-G

Variant names:

• chr1-247425425-T-G
• rs180177457
• NM_001243133.2:c.1976T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP5_Moderate

The NM_001243133.2(NLRP3):​c.1976T>G​(p.Met659Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. M659K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.976

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-247425425-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3251842.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• 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.
• PP5: Variant 1-247425425-T-G is Pathogenic according to our data. Variant chr1-247425425-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 643124.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.1976T>G	p.Met659Arg	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.1976T>G	p.Met659Arg	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryopyrin associated periodic syndrome Pathogenic:1

Mar 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) performed at Invitae indicates that this missense variant is expected to disrupt NLRP3 protein function. This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 661 of the NLRP3 protein (p.Met661Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of cryopyrin-associated periodic syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 643124). This variant disrupts the p.Met661 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 16081838, 24773462), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	.;D;D;.;.;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D;D;D;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;.;D
Polyphen		1.0	D;D;D;D;D;.;.;P
Vest4		0.84
MutPred		0.44		Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);Gain of catalytic residue at M661 (P = 0.0092);
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.91
gMVP		0.82

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: rs180177457; hg19: chr1-247588727;