rs147946775
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001243133.2(NLRP3):āc.2176A>Gā(p.Ser726Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,614,100 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S726T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001243133.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP3 | NM_001243133.2 | c.2176A>G | p.Ser726Gly | missense_variant | 5/10 | ENST00000336119.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP3 | ENST00000336119.8 | c.2176A>G | p.Ser726Gly | missense_variant | 5/10 | 1 | NM_001243133.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000467 AC: 71AN: 152104Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000521 AC: 131AN: 251454Hom.: 1 AF XY: 0.000567 AC XY: 77AN XY: 135894
GnomAD4 exome AF: 0.000945 AC: 1382AN: 1461878Hom.: 2 Cov.: 32 AF XY: 0.000908 AC XY: 660AN XY: 727240
GnomAD4 genome ? AF: 0.000466 AC: 71AN: 152222Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 26AN XY: 74446
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 18, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2021 | This variant is associated with the following publications: (PMID: 25821352) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | NLRP3: BP4, BS1, BS2 - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2018 | The p.Ser728Gly variant is classified as likely benign because it has been ident ified in 0.08% (105/126674) of European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147946775). It has bee n reported in one individual with PFAPA, but was also identified in 2 unaffected family members (Perko 2015). ACMG/AMP Criteria applied: BS1. - |
Familial cold autoinflammatory syndrome 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | May 20, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
NLRP3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 23, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cryopyrin associated periodic syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Familial amyloid nephropathy with urticaria AND deafness Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Autoinflammatory syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
Chronic infantile neurological, cutaneous and articular syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at