rs3926687

Variant names:

• chr17-5589116-G-A
• rs3926687
• ENST00000576905.6:c.-354-4616C>T

Variant summary

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

The ENST00000576905.6(NLRP1):​c.-354-4616C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,142 control chromosomes in the GnomAD database, including 10,631 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 0.34 (10631 hom., cov: 32)
• Consequence: NLRP1 ENST00000576905.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830
• Publications: 12 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000576905.6	c.-354-4616C>T		intron_variant	Intron 1 of 17	4		ENSP00000458303.2
NLRP1	ENST00000572143.2	n.-543-4616C>T		intron_variant	Intron 1 of 17	4		ENSP00000514476.1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52119 AN: 152024 Hom.: 10625 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.343 AC: 52156 AN: 152142 Hom.: 10631 Cov.: 32 AF XY: 0.341 AC XY: 25351 AN XY: 74360

African (AFR) AF: 0.149 AC: 6199 AN: 41522

American (AMR) AF: 0.401 AC: 6136 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3468

East Asian (EAS) AF: 0.0299 AC: 155 AN: 5182

South Asian (SAS) AF: 0.220 AC: 1062 AN: 4826

European-Finnish (FIN) AF: 0.454 AC: 4801 AN: 10570

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30810 AN: 67968

Other (OTH) AF: 0.359 AC: 759 AN: 2114

Alfa AF: 0.422 Hom.: 23380

Bravo AF: 0.331

Asia WGS AF: 0.147 AC: 513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.74
DANN	Benign	0.48
PhyloP100		-0.083

Splicing

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

Other links and lift over

dbSNP: rs3926687; hg19: chr17-5492436;