chr1-247424912-G-C

Variant names:

• chr1-247424912-G-C
• rs145268073
• NM_001243133.2:c.1463G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001243133.2(NLRP3):​c.1463G>C​(p.Arg488Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R488K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102
• Publications: 27 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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.1463G>C	p.Arg488Thr	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.1463G>C	p.Arg488Thr	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249698 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	.;D;D;.;.;.;.;.
Eigen	Benign	0.030
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.93	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
PhyloP100		0.10
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;.;.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.010	D;D;D;D;D;.;.;D
Polyphen		0.98	D;D;D;D;D;.;.;D
Vest4		0.53
MutPred		0.58		Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);Loss of catalytic residue at R490 (P = 0.0479);
MVP		1.0
MPC		1.6
ClinPred		0.65	D
GERP RS		4.2
Varity_R		0.69
gMVP		0.82
Mutation Taster		=70/30	polymorphism

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: rs145268073; hg19: chr1-247588214;