chr17-5617427-A-G

Variant names:

• chr17-5617427-A-G
• rs2733359
• ENST00000576905.6:c.-355+1904T>C

Variant summary

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

The ENST00000576905.6(NLRP1):​c.-355+1904T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 152,052 control chromosomes in the GnomAD database, including 14,560 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 0.43 (14560 hom., cov: 32)
• Consequence: NLRP1 ENST00000576905.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.569
• Publications: 7 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000576905.6. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	ENST00000576905.6	TSL:4	c.-355+1904T>C		intron	N/A	ENSP00000458303.2	Q9C000-2
	NLRP1	ENST00000572143.2	TSL:4	n.-544+1904T>C		intron	N/A	ENSP00000514476.1	A0A8V8TNH7
	NLRP1	ENST00000699639.1		n.84+1904T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65869 AN: 151934 Hom.: 14536 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.427

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

GnomAD4 genome AF: 0.434 AC: 65951 AN: 152052 Hom.: 14560 Cov.: 32 AF XY: 0.432 AC XY: 32133 AN XY: 74318

African (AFR) AF: 0.423 AC: 17523 AN: 41466

American (AMR) AF: 0.442 AC: 6761 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1599 AN: 3470

East Asian (EAS) AF: 0.178 AC: 922 AN: 5166

South Asian (SAS) AF: 0.404 AC: 1949 AN: 4822

European-Finnish (FIN) AF: 0.439 AC: 4638 AN: 10562

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30987 AN: 67956

Other (OTH) AF: 0.433 AC: 915 AN: 2112

Alfa AF: 0.375 Hom.: 2000

Bravo AF: 0.433

Asia WGS AF: 0.348 AC: 1211 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.79
PhyloP100		0.57

Splicing

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

Other links and lift over

dbSNP: rs2733359; hg19: chr17-5520747;