17-5521666-G-C

Position:

• chr17-5521666-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

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: Genomes: not found (cov: 32)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.267

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]

NLRP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a mutagenesis_site Partial loss of autocatalytic processing (50%) and of IL1B release (50%). (size 0) in uniprot entity NLRP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-5521666-G-C is Pathogenic according to our data. Variant chr17-5521666-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31169415). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.3641C>G	p.Pro1214Arg	missense_variant	13/17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.3641C>G	p.Pro1214Arg	missense_variant	13/17	1	NM_033004.4	ENSP00000460475.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoinflammation with arthritis and dyskeratosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	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 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2022

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. Experimental studies have shown that this missense change affects NLRP1 function (PMID: 30291141). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 393320). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.86	.;D;.;.;.;.;D;T;T;D
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-6.0	D;.;.;D;.;D;.;.;.;D
REVEL	Benign	0.070
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;.;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;D;D;D;D;D;D
Vest4		0.53
MutPred		0.63		.;.;Gain of MoRF binding (P = 0.023);Gain of MoRF binding (P = 0.023);Gain of MoRF binding (P = 0.023);.;.;.;Gain of MoRF binding (P = 0.023);Gain of MoRF binding (P = 0.023);
MVP		0.63
MPC		0.83
ClinPred		0.99	D
GERP RS		0.64
Varity_R		0.58
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057524876; hg19: chr17-5424986;