rs104895564
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1PP5_StrongBS2
The NM_144687.4(NLRP12):c.850C>T(p.Arg284Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144687.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP12 | NM_144687.4 | c.850C>T | p.Arg284Ter | stop_gained | 3/10 | ENST00000324134.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP12 | ENST00000324134.11 | c.850C>T | p.Arg284Ter | stop_gained | 3/10 | 1 | NM_144687.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000440 AC: 67AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251008Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135750
GnomAD4 exome AF: 0.0000670 AC: 98AN: 1461804Hom.: 1 Cov.: 40 AF XY: 0.0000591 AC XY: 43AN XY: 727208
GnomAD4 genome ? AF: 0.000460 AC: 70AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31AN XY: 74446
ClinVar
Submissions by phenotype
Familial cold autoinflammatory syndrome 2 Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Feb 05, 2021 | The inherited c.850C>T(p.Arg284Ter)stop-gained variant identified in exon 3(of 10) of the NLRP12 gene creates a premature translation termination codon and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, loss-of-function is not an established mechanism of disease for NLRP12 related disorder. The p.Arg284Ter variant has 0.0004403 allele frequency in the gnomAD(v3) database across all populations represented in the database (67 out of 152,152 heterozygous alleles, no homozygotes), and 0.001448 allele frequency in the African/African-American sub-population (60 out of 41,450 heterozygous alleles, no homozygotes). Although the variant has been reported in a family affected with hereditary periodic fever syndrome [PMID: 18230725], functional studies show contradictory data regarding potential pathogenicity of this variant [PMID: 18230725; PMID: 21360512]. Given the lack of compelling evidence for its pathogenicity, the inherited c.850C>T(p.Arg284Ter) stop-gained variant identified in the NLRP12geneis reported as a variant of uncertain significance. - |
Pathogenic, flagged submission | literature only | OMIM | Feb 05, 2008 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Arg284*) in the NLRP12 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NLRP12 cause disease. This variant is present in population databases (rs104895564, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of familial cold autoinflammatory syndrome (FCAS) (PMID: 18230725). ClinVar contains an entry for this variant (Variation ID: 1596). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NLRP12 function (PMID: 18230725, 21360512). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 21, 2019 | The NLRP12 c.850C>T; p.Arg284Ter variant (rs104895564) is published in the medical literature in one family with a hereditary periodic fever syndrome (Jeru 2008, Jeru 2011), but has also been reported in a reportedly unaffected individual (Rodriguez-Flores 2014). The variant is reported in the ClinVar database (Variation ID: 1596) and in the African population with an allele frequency of 0.1% (34/24916 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional studies have shown conflicting NFKB activation by this variant (Borghini 2011, Jeru 2008). Although the physiological relevance of NLRP12 in periodic fever syndrome is certain, if disease is caused by loss-of-function variants remained to be determined (Tuncer 2014). Due to conflicting information, the clinical significance of this variant is uncertain. References: Borghini S et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 2011 Mar;63(3):830-9. Jeru I et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. Jeru I et al. Role of interleukin-1ß in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis Rheum. 2011 Jul;63(7):2142-8. Rodriguez-Flores JL et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014 Jan;35(1):105-16. Tuncer S et al. The multifaceted nature of NLRP12. J Leukoc Biol. 2014 Dec;96(6):991-1000. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 05, 2022 | - - |
not provided Pathogenic:1Other:1
Pathogenic, flagged submission | clinical testing | GeneDx | Feb 07, 2023 | Reported in association with NLRP12-related familial cold autoinflammatory syndrome in the published literature (Jeru et al., 2008); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect (Jeru et al., 2008); This variant is associated with the following publications: (PMID: 34054914, 25525159, 21480187, 31589614, 30788684, 32743516, 33525590, 30559449, 24906912, 31820221, 28421071, 27314497, 24123366, 20007570, 21360512, 18230725) - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at