rs1057519493
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_033004.4(NLRP1):c.197C>T(p.Ala66Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/20 in silico tools predict 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 Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NLRP1 | NM_033004.4 | c.197C>T | p.Ala66Val | missense_variant | Exon 1 of 17 | ENST00000572272.6 | NP_127497.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome Pathogenic:1
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not provided Pathogenic:1
The A66V variant in the NLRP1 gene has been reported previously in the heterozygous state in a family with MSPC (Zhong et al., 2016). The A66V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A66V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. While this substitution occurs at a position that is not conserved across species, it is located in the auto-inhibitory pyrin domain (Zhong et al., 2016). Functional studies indicate that cells overexpressing A66V have significantly increased inflammosome assembly compared to wild type, and A66V leads to a disruption in proper protein folding (Zhong et al., 2016). The A66V variant is a strong candidate for a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at