rs771315000
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001243133.2(NLRP3):āc.3037A>Gā(p.Lys1013Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 30)
Exomes š: 0.000039 ( 0 hom. )
Consequence
NLRP3
NM_001243133.2 missense
NM_001243133.2 missense
Scores
1
17
Clinical Significance
Conservation
PhyloP100: 0.919
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 -5 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLRP3. . Gene score misZ 2.1417 (greater than the threshold 3.09). Trascript score misZ 3.5037 (greater than threshold 3.09). GenCC has associacion of gene with familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.08061063).
BS2
High AC in GnomAdExome4 at 57 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NLRP3 | NM_001243133.2 | c.3037A>G | p.Lys1013Glu | missense_variant | 10/10 | ENST00000336119.8 | NP_001230062.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NLRP3 | ENST00000336119.8 | c.3037A>G | p.Lys1013Glu | missense_variant | 10/10 | 1 | NM_001243133.2 | ENSP00000337383.4 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251480Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
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GnomAD4 exome AF: 0.0000390 AC: 57AN: 1460940Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726862
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GnomAD4 genome 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74296
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cold autoinflammatory syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cryopyrin associated periodic syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 07, 2019 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces lysine with glutamic acid at codon 1015 of the NLRP3 protein (p.Lys1015Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs771315000, ExAC 0.001%). This variant has not been reported in the literature in individuals with NLRP3-related disease. ClinVar contains an entry for this variant (Variation ID: 234308). - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2014 | To our knowledge, the K1015E missense substitution has neither been published as a mutation, nor reported as a benign polymorphism. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K1015E represents a non-conservative amino acid substitution as a positively-charged Lysine residue is replaced with a negatively-charged Glutamic Acid residue. However, this substitution occurs at a position in the NLRP3 protein that is only moderately conserved among species and is not located in the NACHT/NBD domain, which is the domain where the vast majority of NLRP3 disease-associated mutations have been identified. Therefore, based on the currently available information, it is unclear whether K1015E is a disease-causing mutation or a rare benign variant. - |
Familial amyloid nephropathy with urticaria AND deafness Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Chronic infantile neurological, cutaneous and articular syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;.;T;T;.;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;.;N
REVEL
Benign
Sift
Benign
T;T;T;T;T;.;T
Sift4G
Benign
T;T;T;T;T;.;T
Polyphen
B;B;B;B;B;.;B
Vest4
MutPred
0.46
.;Loss of ubiquitination at K1015 (P = 0.0071);Loss of ubiquitination at K1015 (P = 0.0071);.;.;.;.;
MVP
MPC
0.65
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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