1-247429697-G-C

Variant names:

• chr1-247429697-G-C
• rs180177469
• NM_001243133.2:c.2263G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001243133.2(NLRP3):​c.2263G>C​(p.Gly755Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G755A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.25

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 Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_001243133.2 (NLRP3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2203018
• PM1: In a helix (size 11) in uniprot entity NLRP3_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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 chr1-247429698-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97959.Status of the report is criteria_provided_single_submitter, 1 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, 0.893
• PP5: Variant 1-247429697-G-C is Pathogenic according to our data. Variant chr1-247429697-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97958.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-247429697-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.2263G>C	p.Gly755Arg	missense_variant	Exon 5 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.2263G>C	p.Gly755Arg	missense_variant	Exon 5 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic infantile neurological, cutaneous and articular syndrome Pathogenic:1

Sep 13, 2022

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant (also described as p.G755R in literature) has been identified in patient cohorts with cryopyrin-associated periodic syndromes (PMID:16449034, PMID:18080732). Additionally, a different amino acid change at this residue (p.G755A) has been previously reported in individual(s) with NOMID-CINCA syndrome (PMID:16871551), suggesting this residue is sensitive to variation. The p.G757R variant is absent from population databases, such as the Genome Aggregation Database (gnomad). ClinVar contains an entry for this variant (Variation ID: 97958). In silico tools predict that this variant is deleterious; however, these predictions have not been tested directly. Based on currently available evidence, we consider the p.G757R variant to be likely pathogenic. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.4	D;D;D;D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.
Polyphen		0.59	P;D;D;P;.
Vest4		0.88
MutPred		0.59		Gain of methylation at G757 (P = 0.0502);Gain of methylation at G757 (P = 0.0502);Gain of methylation at G757 (P = 0.0502);Gain of methylation at G757 (P = 0.0502);Gain of methylation at G757 (P = 0.0502);
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.78

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: rs180177469; hg19: chr1-247592999;