1-247421341-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5BP4BA1

The NM_001243133.2(NLRP3):​c.278-1889G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 151,816 control chromosomes in the GnomAD database, including 25,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

Frequency

Genomes: 𝑓 0.58 ( 25408 hom., cov: 30)

Consequence

NLRP3
NM_001243133.2 intron

Scores

2

Clinical Significance

Likely risk allele no assertion criteria provided P:1

Conservation

PhyloP100: -1.24
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP5
Variant 1-247421341-G-C is Pathogenic according to our data. Variant chr1-247421341-G-C is described in ClinVar as [Likely_risk_allele]. Clinvar id is 2687869.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9). . Strength limited to SUPPORTING due to the PP5.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NLRP3NM_001243133.2 linkc.278-1889G>C intron_variant Intron 2 of 9 ENST00000336119.8 NP_001230062.1 Q96P20A0A7I2R3P8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NLRP3ENST00000336119.8 linkc.278-1889G>C intron_variant Intron 2 of 9 1 NM_001243133.2 ENSP00000337383.4 A0A7I2R3P8

Frequencies

GnomAD3 genomes
AF:
0.576
AC:
87379
AN:
151698
Hom.:
25395
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.489
Gnomad AMI
AF:
0.670
Gnomad AMR
AF:
0.599
Gnomad ASJ
AF:
0.613
Gnomad EAS
AF:
0.624
Gnomad SAS
AF:
0.577
Gnomad FIN
AF:
0.605
Gnomad MID
AF:
0.680
Gnomad NFE
AF:
0.612
Gnomad OTH
AF:
0.593
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.576
AC:
87436
AN:
151816
Hom.:
25408
Cov.:
30
AF XY:
0.578
AC XY:
42856
AN XY:
74200
show subpopulations
Gnomad4 AFR
AF:
0.489
Gnomad4 AMR
AF:
0.598
Gnomad4 ASJ
AF:
0.613
Gnomad4 EAS
AF:
0.624
Gnomad4 SAS
AF:
0.578
Gnomad4 FIN
AF:
0.605
Gnomad4 NFE
AF:
0.612
Gnomad4 OTH
AF:
0.592
Alfa
AF:
0.585
Hom.:
3258
Bravo
AF:
0.576
Asia WGS
AF:
0.584
AC:
2033
AN:
3478

ClinVar

Significance: Likely risk allele
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Long COVID-19 Pathogenic:1
-
DECIPHERD-UDD, Universidad del Desarrollo
Significance: Likely risk allele
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.46
DANN
Benign
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs10754555; hg19: chr1-247584643; API