rs146932154

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033004.4(NLRP1):c.3551T>C(p.Met1184Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,612,142 control chromosomes in the GnomAD database, including 1,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1184A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.020 ( 240 hom., cov: 32)

Exomes 𝑓: 0.012 ( 1481 hom. )

Consequence

NLRP1
NM_033004.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.90

Publications

6 publications found

Variant links:

COSMIC-nc: COSV52559162

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

NLRP1 links:

LOC124903902 (HGNC:):

LOC124903902 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015281439).

BP6

Variant 17-5521756-A-G is Benign according to our data. Variant chr17-5521756-A-G is described in ClinVar as Benign. ClinVar VariationId is 403239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4 link	c.3551T>C	p.Met1184Thr	missense_variant	Exon 13 of 17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6 link	c.3551T>C	p.Met1184Thr	missense_variant	Exon 13 of 17	1	NM_033004.4	ENSP00000460475.1		Q9C000-1

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3034

AN:

152190

Hom.:

239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00614

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0383

AC:

9583

AN:

250332

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.00390

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000741

Gnomad NFE exome

AF:

0.00588

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0125

AC:

18213

AN:

1459834

Hom.:

1481

Cov.:

AF XY:

0.0111

AC XY:

8088

AN XY:

726184

show subpopulations

African (AFR)

AF:

0.00287

AC:

AN:

33432

American (AMR)

AF:

0.233

AC:

10391

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00150

AC:

AN:

26064

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00443

AC:

382

AN:

86140

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00320

AC:

AN:

4686

European-Non Finnish (NFE)

AF:

0.00601

AC:

6676

AN:

1111516

Other (OTH)

AF:

0.00923

AC:

556

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

854

1708

2562

3416

4270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

358

716

1074

1432

1790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0200

AC:

3042

AN:

152308

Hom.:

240

Cov.:

AF XY:

0.0223

AC XY:

1664

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00409

AC:

170

AN:

41586

American (AMR)

AF:

0.153

AC:

2344

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00540

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00613

AC:

417

AN:

68016

Other (OTH)

AF:

0.0171

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

136

272

409

545

681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00874

Hom.:

104

Bravo

AF:

0.0315

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.0284

AC:

3447

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00605

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0059

.;.;.;.;T;.;.;.;T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.76

.;T;.;.;.;.;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

1.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.71

N;.;.;N;.;N;.;.;.;N

REVEL

Benign

0.042

Sift

Uncertain

0.0030

D;.;.;D;.;D;.;.;.;D

Sift4G

Uncertain

0.012

D;D;.;D;D;D;D;D;D;D

Polyphen

0.0, 0.0010

.;.;B;B;B;B;B;B;B;B

Vest4

0.086

MPC

0.24

ClinPred

0.0078

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.21

gMVP

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over