rs9900356

Variant names:

• chr17-5515958-C-T
• rs9900356
• NM_033004.4:c.4058-441G>A

Variant summary

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

The NM_033004.4(NLRP1):​c.4058-441G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 152,178 control chromosomes in the GnomAD database, including 52,224 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 0.83 (52224 hom., cov: 33)
• Consequence: NLRP1 NM_033004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0880
• Publications: 6 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 (AFR) allele frequency at 95% confidence interval = 0.888 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.4058-441G>A		intron	N/A	NP_127497.1
	NLRP1	NM_033006.4		c.3968-441G>A		intron	N/A	NP_127499.1
	NLRP1	NM_014922.5		c.3926-441G>A		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.4058-441G>A		intron	N/A	ENSP00000460475.1
	NLRP1	ENST00000354411.8	TSL:1	c.3968-441G>A		intron	N/A	ENSP00000346390.3
	NLRP1	ENST00000269280.9	TSL:1	c.3926-441G>A		intron	N/A	ENSP00000269280.4

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125671 AN: 152060 Hom.: 52175 Cov.: 33

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.884

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.784

Gnomad OTH AF: 0.794

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

GnomAD4 genome AF: 0.827 AC: 125777 AN: 152178 Hom.: 52224 Cov.: 33 AF XY: 0.830 AC XY: 61744 AN XY: 74404

African (AFR) AF: 0.896 AC: 37183 AN: 41516

American (AMR) AF: 0.800 AC: 12219 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2610 AN: 3470

East Asian (EAS) AF: 0.884 AC: 4583 AN: 5186

South Asian (SAS) AF: 0.820 AC: 3958 AN: 4828

European-Finnish (FIN) AF: 0.870 AC: 9213 AN: 10588

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.784 AC: 53326 AN: 67996

Other (OTH) AF: 0.798 AC: 1684 AN: 2110

Alfa AF: 0.800 Hom.: 83132

Bravo AF: 0.823

Asia WGS AF: 0.868 AC: 3020 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-0.088
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: rs9900356; hg19: chr17-5419278;