rs12150220

Variant names:

• chr17-5582047-A-T
• rs12150220
• NM_033004.4:c.464T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033004.4(NLRP1):​c.464T>A​(p.Leu155His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,610,836 control chromosomes in the GnomAD database, including 142,729 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10309 hom., cov: 32)
  • Exomes 𝑓: 0.41 (132420 hom.)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.19
• Publications: 115 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.975894E-4).
• BP6: Variant 17-5582047-A-T is Benign according to our data. Variant chr17-5582047-A-T is described in ClinVar as Benign. ClinVar VariationId is 4163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 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.464T>A	p.Leu155His	missense	Exon 3 of 17	NP_127497.1	Q9C000-1
	NLRP1	NM_033006.4		c.464T>A	p.Leu155His	missense	Exon 3 of 16	NP_127499.1	Q9C000-4
	NLRP1	NM_014922.5		c.464T>A	p.Leu155His	missense	Exon 3 of 16	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.464T>A	p.Leu155His	missense	Exon 3 of 17	ENSP00000460475.1	Q9C000-1
	NLRP1	ENST00000354411.8	TSL:1	c.464T>A	p.Leu155His	missense	Exon 3 of 16	ENSP00000346390.3	Q9C000-4
	NLRP1	ENST00000269280.9	TSL:1	c.464T>A	p.Leu155His	missense	Exon 4 of 17	ENSP00000269280.4	Q9C000-2

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49953 AN: 151962 Hom.: 10308 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.366 AC: 90395 AN: 246982 AF XY: 0.366

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.0251

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.414 AC: 603617 AN: 1458756 Hom.: 132420 Cov.: 36 AF XY: 0.410 AC XY: 297448 AN XY: 725724

African (AFR) AF: 0.0846 AC: 2829 AN: 33428

American (AMR) AF: 0.412 AC: 18189 AN: 44184

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 12292 AN: 26044

East Asian (EAS) AF: 0.0322 AC: 1277 AN: 39654

South Asian (SAS) AF: 0.233 AC: 20088 AN: 86128

European-Finnish (FIN) AF: 0.454 AC: 24237 AN: 53338

Middle Eastern (MID) AF: 0.405 AC: 2327 AN: 5752

European-Non Finnish (NFE) AF: 0.450 AC: 499138 AN: 1109974

Other (OTH) AF: 0.386 AC: 23240 AN: 60254

GnomAD4 genome AF: 0.329 AC: 49963 AN: 152080 Hom.: 10309 Cov.: 32 AF XY: 0.327 AC XY: 24306 AN XY: 74316

African (AFR) AF: 0.101 AC: 4177 AN: 41516

American (AMR) AF: 0.394 AC: 6016 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1601 AN: 3464

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5180

South Asian (SAS) AF: 0.220 AC: 1061 AN: 4822

European-Finnish (FIN) AF: 0.454 AC: 4793 AN: 10562

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30801 AN: 67958

Other (OTH) AF: 0.348 AC: 732 AN: 2106

Alfa AF: 0.427 Hom.: 11161

Bravo AF: 0.314

TwinsUK AF: 0.431 AC: 1598

ALSPAC AF: 0.464 AC: 1790

ESP6500AA AF: 0.0992 AC: 437

ESP6500EA AF: 0.452 AC: 3884

ExAC AF: 0.359 AC: 43605

Asia WGS AF: 0.142 AC: 497 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoinflammation with arthritis and dyskeratosis (1)
-	-	1	Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (1)
-	-	1	not specified (1)
-	-	1	Respiratory papillomatosis, juvenile recurrent, congenital (1)
-	-	-	Vitiligo-associated multiple autoimmune disease susceptibility 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.8
DANN	Benign	0.89
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00020	T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.084
Sift	Benign	0.060	T
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.49
ClinPred		0.013	T
GERP RS		-1.1
Varity_R		0.049
gMVP		0.26
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: rs12150220; hg19: chr17-5485367; COSMIC: COSV52559734; COSMIC: COSV52559734;