17-5509041-C-T

Variant names:

• chr17-5509041-C-T
• rs8079034
• ENST00000574512.1:n.821-3064G>A

Variant summary

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

The ENST00000574512.1(NLRP1):​n.821-3064G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,140 control chromosomes in the GnomAD database, including 4,856 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 0.24 (4856 hom., cov: 33)
• Consequence: NLRP1 ENST00000574512.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312
• Publications: 23 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 (AFR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_001033053.3	c.4070-7169G>A		intron_variant	Intron 15 of 15		NP_001028225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000574512.1	n.821-3064G>A		intron_variant	Intron 1 of 1	1
NLRP1	ENST00000699613.1	c.4102+6432G>A		intron_variant	Intron 16 of 16			ENSP00000514477.1
NLRP1	ENST00000262467.11	c.4070-7169G>A		intron_variant	Intron 15 of 15	5		ENSP00000262467.5

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36255 AN: 152022 Hom.: 4845 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.239 AC: 36318 AN: 152140 Hom.: 4856 Cov.: 33 AF XY: 0.236 AC XY: 17590 AN XY: 74398

African (AFR) AF: 0.374 AC: 15510 AN: 41478

American (AMR) AF: 0.174 AC: 2657 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3470

East Asian (EAS) AF: 0.162 AC: 840 AN: 5186

South Asian (SAS) AF: 0.173 AC: 835 AN: 4834

European-Finnish (FIN) AF: 0.211 AC: 2232 AN: 10596

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13138 AN: 67980

Other (OTH) AF: 0.203 AC: 428 AN: 2112

Alfa AF: 0.167 Hom.: 681

Bravo AF: 0.242

Asia WGS AF: 0.162 AC: 565 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.1
DANN	Benign	0.42
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs8079034; hg19: chr17-5412361; COSMIC: COSV52561840; COSMIC: COSV52561840;