chr17-5517008-C-T

Variant names:

• chr17-5517008-C-T
• rs6502867
• NM_033004.4:c.4057+738G>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.4057+738G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 152,230 control chromosomes in the GnomAD database, including 51,387 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 0.82 (51387 hom., cov: 32)
• Consequence: NLRP1 NM_033004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• Publications: 32 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	NM_033004.4	MANE Select	c.4057+738G>A		intron	N/A	NP_127497.1	Q9C000-1
	NLRP1	NM_033006.4		c.3967+738G>A		intron	N/A	NP_127499.1	Q9C000-4
	NLRP1	NM_014922.5		c.3925+738G>A		intron	N/A	NP_055737.1	Q9C000-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	ENST00000572272.6	TSL:1 MANE Select	c.4057+738G>A		intron	N/A	ENSP00000460475.1	Q9C000-1
	NLRP1	ENST00000354411.8	TSL:1	c.3967+738G>A		intron	N/A	ENSP00000346390.3	Q9C000-4
	NLRP1	ENST00000269280.9	TSL:1	c.3925+738G>A		intron	N/A	ENSP00000269280.4	Q9C000-2

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124483 AN: 152112 Hom.: 51327 Cov.: 32

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.819 AC: 124607 AN: 152230 Hom.: 51387 Cov.: 32 AF XY: 0.822 AC XY: 61223 AN XY: 74436

African (AFR) AF: 0.911 AC: 37851 AN: 41534

American (AMR) AF: 0.788 AC: 12046 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2458 AN: 3468

East Asian (EAS) AF: 0.968 AC: 5022 AN: 5190

South Asian (SAS) AF: 0.836 AC: 4034 AN: 4824

European-Finnish (FIN) AF: 0.829 AC: 8781 AN: 10590

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51840 AN: 68020

Other (OTH) AF: 0.779 AC: 1646 AN: 2112

Alfa AF: 0.771 Hom.: 76244

Bravo AF: 0.818

Asia WGS AF: 0.899 AC: 3126 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.6
DANN	Benign	0.64
PhyloP100		-0.29
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: rs6502867; hg19: chr17-5420328; COSMIC: COSV52561912; COSMIC: COSV52561912;