rs104895566
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_144687.4(NLRP12):c.1343G>C(p.Gly448Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,613,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G448R) has been classified as Uncertain significance.
Frequency
Consequence
NM_144687.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP12 | NM_144687.4 | c.1343G>C | p.Gly448Ala | missense_variant | 3/10 | ENST00000324134.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP12 | ENST00000324134.11 | c.1343G>C | p.Gly448Ala | missense_variant | 3/10 | 1 | NM_144687.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250486Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135596
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461496Hom.: 1 Cov.: 40 AF XY: 0.0000839 AC XY: 61AN XY: 727056
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74246
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | - - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2017 | The G448A variant in the NLRP12 gene has been reported in an individual with late onset autoinflammatory disorder (Vitale et al., 2013). The G448A variant is observed in 7/65966 (0.011%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The G448A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G448A as a variant of uncertain significance, which may be related to the reported rash, migraine, and pain in this individual. - |
Familial cold autoinflammatory syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 448 of the NLRP12 protein (p.Gly448Ala). This variant is present in population databases (rs104895566, gnomAD 0.01%). This missense change has been observed in individual(s) with chronic NLRP12-autoinflammatory disorder (PMID: 24064030). ClinVar contains an entry for this variant (Variation ID: 97886). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NLRP12 protein function with a negative predictive value of 80%. 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 | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | NLRP12 NM_144687 exon 3 p.Gly448Ala (c.1343G>C): This variant has not been reported in the literature but is present in 12/126260 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs104895566). This variant is present in ClinVar (Variation ID:97886). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at