rs117287351
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001243133.2(NLRP3):c.208G>A(p.Val70Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,613,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. V70L) 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.208G>A | p.Val70Met | missense_variant | 2/10 | ENST00000336119.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP3 | ENST00000336119.8 | c.208G>A | p.Val70Met | missense_variant | 2/10 | 1 | NM_001243133.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000440 AC: 67AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000759 AC: 190AN: 250408Hom.: 0 AF XY: 0.000717 AC XY: 97AN XY: 135322
GnomAD4 exome AF: 0.000421 AC: 616AN: 1461662Hom.: 4 Cov.: 31 AF XY: 0.000396 AC XY: 288AN XY: 727106
GnomAD4 genome ? AF: 0.000440 AC: 67AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2021 | This variant is associated with the following publications: (PMID: 28028683, 23633568, 31172726, 28956000, 31664448, 33329557, 32115236) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | NLRP3: BP4, BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 08, 2017 | The NLRP3 c.214G>A;p.Val72Met variant has been listed in the medical literature in at least two individuals with autoinflammatory disease (Nakayama 2017). The variant is listed in the ClinVar database (Variation ID: 245593) and in the dbSNP variant database (rs117287351) with an allele frequency of up to 0.9 percent (171/18868 alleles) in East Asians in the Genome Aggregation Database. The amino acid at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, the clinical significance cannot be determined with certainty. If this variant is later determined to be pathogenic, this individual is predicted to be affected with autosomal dominant CINCA syndrome, Familial cold-induced inflammatory syndrome, or Muckle-Wells syndrome (OMIM#606416). References: Nakayama M et al. Accurate clinical genetic testing for autoinflammatory diseases using the next-generation sequencing platform MiSeq. Biochem Biophys Rep 2017 9:146-152. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 23, 2017 | p.Val72Met in exon 1 of NLRP3: This variant is not expected to have clinical significance because it has been identified in 0.81% (70/8600) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs117287351). - |
Familial cold autoinflammatory syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cryopyrin associated periodic syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Autoinflammatory syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 17, 2021 | - - |
Familial amyloid nephropathy with urticaria AND deafness Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Chronic infantile neurological, cutaneous and articular syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination 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