NM_033004.4:c.2529-1269C>T

Variant names:

• chr17-5543296-G-A
• rs9889625
• NM_033004.4:c.2529-1269C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033004.4(NLRP1):​c.2529-1269C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 152,146 control chromosomes in the GnomAD database, including 7,983 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7983 hom., cov: 31)
• Consequence: NLRP1 NM_033004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• autoinflammation with arthritis and dyskeratosis

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	NM_033004.4	MANE Select	c.2529-1269C>T		intron	N/A	NP_127497.1
	NLRP1	NM_033006.4		c.2529-1269C>T		intron	N/A	NP_127499.1
	NLRP1	NM_014922.5		c.2529-1269C>T		intron	N/A	NP_055737.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	ENST00000572272.6	TSL:1 MANE Select	c.2529-1269C>T		intron	N/A	ENSP00000460475.1
	NLRP1	ENST00000354411.8	TSL:1	c.2529-1269C>T		intron	N/A	ENSP00000346390.3
	NLRP1	ENST00000269280.9	TSL:1	c.2529-1269C>T		intron	N/A	ENSP00000269280.4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43572 AN: 152028 Hom.: 7982 Cov.: 31

Gnomad AFR AF: 0.0741

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.289

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.286 AC: 43583 AN: 152146 Hom.: 7983 Cov.: 31 AF XY: 0.288 AC XY: 21401 AN XY: 74372

African (AFR) AF: 0.0738 AC: 3068 AN: 41550

American (AMR) AF: 0.363 AC: 5552 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1309 AN: 3472

East Asian (EAS) AF: 0.0245 AC: 127 AN: 5174

South Asian (SAS) AF: 0.219 AC: 1054 AN: 4820

European-Finnish (FIN) AF: 0.411 AC: 4341 AN: 10554

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27063 AN: 67978

Other (OTH) AF: 0.285 AC: 601 AN: 2108

Alfa AF: 0.238 Hom.: 873

Bravo AF: 0.272

Asia WGS AF: 0.131 AC: 458 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.1
DANN	Benign	0.65
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs9889625; hg19: chr17-5446616;