chr17-5509153-A-C

Variant names:

• chr17-5509153-A-C
• rs8079727
• ENST00000574512.1:n.821-3176T>G

Variant summary

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

The NM_001033053.3(NLRP1):​c.4070-7281T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,028 control chromosomes in the GnomAD database, including 7,850 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 0.31 (7850 hom., cov: 32)
• Consequence: NLRP1 NM_001033053.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 20 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033053.3. 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_001033053.3		c.4070-7281T>G		intron	N/A	NP_001028225.1	Q9C000-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	ENST00000574512.1	TSL:1	n.821-3176T>G		intron	N/A
	NLRP1	ENST00000699613.1		c.4102+6320T>G		intron	N/A	ENSP00000514477.1	A0A8V8TNP3
	NLRP1	ENST00000262467.11	TSL:5	c.4070-7281T>G		intron	N/A	ENSP00000262467.5	Q9C000-5

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46551 AN: 151910 Hom.: 7810 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.307 AC: 46655 AN: 152028 Hom.: 7850 Cov.: 32 AF XY: 0.307 AC XY: 22801 AN XY: 74300

African (AFR) AF: 0.456 AC: 18911 AN: 41470

American (AMR) AF: 0.191 AC: 2922 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 769 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1496 AN: 5158

South Asian (SAS) AF: 0.309 AC: 1490 AN: 4824

European-Finnish (FIN) AF: 0.288 AC: 3042 AN: 10576

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17108 AN: 67946

Other (OTH) AF: 0.271 AC: 572 AN: 2108

Alfa AF: 0.248 Hom.: 3769

Bravo AF: 0.305

Asia WGS AF: 0.336 AC: 1171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.53
PhyloP100		-1.0
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: rs8079727; hg19: chr17-5412473; COSMIC: COSV52561847; COSMIC: COSV52561847;