rs1057524876

Positions:

• chr17-5521666-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate 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 (★). Synonymous variant affecting the same amino acid position (i.e. P1214P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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]

LOC124903902 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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_single_submitter, 1 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	UniProt
NLRP1	NM_033004.4	c.3641C>G	p.Pro1214Arg	missense_variant	13/17	ENST00000572272.6
LOC124903902	XR_007065590.1	n.250+3581G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP1	ENST00000572272.6	c.3641C>G	p.Pro1214Arg	missense_variant	13/17	1	NM_033004.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autoinflammation with arthritis and dyskeratosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 25, 2023

- -

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
MutationTaster	Benign	1.0	N;N;N;N;N;N
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;