rs1057519493
Positions:
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
Genomes: not found (cov: 33)
Consequence
NLRP1
NM_033004.4 missense
NM_033004.4 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: -0.164
Genes affected
NLRP1 (HGNC:14374): (NLR family pyrin domain containing 1) This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-5583761-G-A is Pathogenic according to our data. Variant chr17-5583761-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375414.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NLRP1 | NM_033004.4 | c.197C>T | p.Ala66Val | missense_variant | 1/17 | ENST00000572272.6 | NP_127497.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NLRP1 | ENST00000572272.6 | c.197C>T | p.Ala66Val | missense_variant | 1/17 | 1 | NM_033004.4 | ENSP00000460475.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 30, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2017 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T;.;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;.;.;.;.;T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.;N;.;.;.;N
REVEL
Benign
Sift
Uncertain
D;.;.;D;.;D;.;.;.;D
Sift4G
Uncertain
D;D;.;D;D;T;D;T;D;D
Polyphen
0.94, 0.95
.;.;P;P;P;P;P;P;P;P
Vest4
MutPred
Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);Gain of MoRF binding (P = 0.0945);
MVP
MPC
0.70
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at