rs1057519493

chr17-5583761-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

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	UniProt
NLRP1	NM_033004.4	c.197C>T	p.Ala66Val	missense_variant	1/17	ENST00000572272.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP1	ENST00000572272.6	c.197C>T	p.Ala66Val	missense_variant	1/17	1	NM_033004.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.042	N
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;.;.;N;.;N;.;.;.;N
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D;.;.;D;.;D;.;.;.;D
Sift4G	Uncertain	0.010	D;D;.;D;D;T;D;T;D;D
Polyphen		0.94, 0.95	.;.;P;P;P;P;P;P;P;P
Vest4		0.31
MutPred		0.79		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		0.76
MPC		0.70
ClinPred		0.82	D
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.77

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: rs1057519493; hg19: chr17-5487081;