rs1057519493

Variant names:

• chr17-5583761-G-A
• rs1057519493
• NM_033004.4:c.197C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000573522: 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).".

• 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
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

  Inheritance: AD, SD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autoinflammation with arthritis and dyskeratosis

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000573522: 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).
• 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 VariationId is 375414.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033004.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	NM_033004.4	MANE Select	c.197C>T	p.Ala66Val	missense	Exon 1 of 17	NP_127497.1	Q9C000-1
	NLRP1	NM_033006.4		c.197C>T	p.Ala66Val	missense	Exon 1 of 16	NP_127499.1	Q9C000-4
	NLRP1	NM_014922.5		c.197C>T	p.Ala66Val	missense	Exon 1 of 16	NP_055737.1	Q9C000-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	ENST00000572272.6	TSL:1 MANE Select	c.197C>T	p.Ala66Val	missense	Exon 1 of 17	ENSP00000460475.1	Q9C000-1
	NLRP1	ENST00000354411.8	TSL:1	c.197C>T	p.Ala66Val	missense	Exon 1 of 16	ENSP00000346390.3	Q9C000-4
	NLRP1	ENST00000269280.9	TSL:1	c.197C>T	p.Ala66Val	missense	Exon 2 of 17	ENSP00000269280.4	Q9C000-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.74	T
PhyloP100		-0.16
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.94	P
Vest4		0.31
MutPred		0.79		Gain of MoRF binding (P = 0.0945)
MVP		0.76
MPC		0.70
ClinPred		0.82	D
GERP RS		0.36
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.77
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519493; hg19: chr17-5487081;