17-5521666-G-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4
The NM_033004.4(NLRP1):c.3641C>G(p.Pro1214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_033004.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NLRP1 | NM_033004.4 | c.3641C>G | p.Pro1214Arg | missense_variant | Exon 13 of 17 | ENST00000572272.6 | NP_127497.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autoinflammation with arthritis and dyskeratosis Pathogenic:2
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autoinflammation with arthritis and dyskeratosis (MIM#617388) and palmoplantar carcinoma, multiple self-healing (MIM#615225). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FIIND domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Pro1214Leu) has been observed as de novo in an individual with Papillon-Lefevre syndrome and palmoplantar keratosis and periodontitis (PMID: 33738798). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by a clinical laboratory in ClinVar. This variant has also been observed as de novo in an individual with congenital and progressive disseminated follicular hyperkeratosis (PMID: 27965258). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant causes loss of NLRP1-FIIND and DPP9 binding, abolishing the repression of DPP9 on the NLRP1 inflammasome (PMID: 30291141). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:1
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1214 of the NLRP1 protein (p.Pro1214Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NLRP1-gain of function syndrome (PMID: 27965258). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 393320). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NLRP1 function (PMID: 30291141). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at