chr1-247418855-G-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP5_ModerateBS2
The NM_001243133.2(NLRP3):c.55G>C(p.Asp19His) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
NLRP3
NM_001243133.2 missense
NM_001243133.2 missense
Scores
2
10
5
Clinical Significance
Conservation
PhyloP100: 4.80
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, NLRP3
PP5
?
Variant 1-247418855-G-C is Pathogenic according to our data. Variant chr1-247418855-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495298.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High AC in GnomAdExome at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP3 | NM_001243133.2 | c.55G>C | p.Asp19His | missense_variant | 2/10 | ENST00000336119.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP3 | ENST00000336119.8 | c.55G>C | p.Asp19His | missense_variant | 2/10 | 1 | NM_001243133.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251292Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135872
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727238
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74404
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Keratitis fugax hereditaria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Likely Pathogenic, for Keratitis fugax hereditaria, autosomal dominant. The following ACMG Tag(s) were applied: PP1-Strong => PP1 upgraded in strength to Strong (https://www.ncbi.nlm.nih.gov/pubmed/29366613). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM2-Supporting => PM2 downgraded in strength to Supporting. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 27, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;D;D;.;D;D;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;.;.;D
Sift4G
Uncertain
D;D;D;D;D;.;.;D
Polyphen
D;D;D;D;D;.;.;D
Vest4
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at