rs11651270

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.3550A>G(p.Met1184Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,610,340 control chromosomes in the GnomAD database, including 169,620 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 (★★). 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 0.47 ( 17007 hom., cov: 32)

Exomes 𝑓: 0.46 ( 152613 hom. )

Consequence

NLRP1
NM_033004.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.546

Publications

78 publications found

Variant links:

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=3.0520558E-4).

BP6

Variant 17-5521757-T-C is Benign according to our data. Variant chr17-5521757-T-C is described in ClinVar as Benign. ClinVar VariationId is 403240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4 link	c.3550A>G	p.Met1184Val	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.3550A>G	p.Met1184Val	missense_variant	Exon 13 of 17	1	NM_033004.4	ENSP00000460475.1		Q9C000-1

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71404

AN:

151966

Hom.:

16966

Cov.:

show subpopulations

Gnomad AFR

AF:

0.507

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.467

Gnomad ASJ

AF:

0.513

Gnomad EAS

AF:

0.250

Gnomad SAS

AF:

0.421

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.467

Gnomad OTH

AF:

0.458

GnomAD2 exomes

AF:

0.449

AC:

112339

AN:

250088

AF XY:

0.448

show subpopulations

Gnomad AFR exome

AF:

0.512

Gnomad AMR exome

AF:

0.460

Gnomad ASJ exome

AF:

0.517

Gnomad EAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.468

Gnomad OTH exome

AF:

0.468

GnomAD4 exome

AF:

0.455

AC:

663905

AN:

1458256

Hom.:

152613

Cov.:

AF XY:

0.455

AC XY:

329807

AN XY:

725370

show subpopulations

African (AFR)

AF:

0.511

AC:

17068

AN:

33386

American (AMR)

AF:

0.457

AC:

20391

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.518

AC:

13489

AN:

26022

East Asian (EAS)

AF:

0.262

AC:

10394

AN:

39660

South Asian (SAS)

AF:

0.424

AC:

36514

AN:

86108

European-Finnish (FIN)

AF:

0.464

AC:

24768

AN:

53354

Middle Eastern (MID)

AF:

0.449

AC:

2059

AN:

4588

European-Non Finnish (NFE)

AF:

0.461

AC:

511682

AN:

1110286

Other (OTH)

AF:

0.458

AC:

27540

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

17929

35857

53786

71714

89643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15166

30332

45498

60664

75830

<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:

0.470

AC:

71509

AN:

152084

Hom.:

17007

Cov.:

AF XY:

0.470

AC XY:

34949

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.507

AC:

21036

AN:

41482

American (AMR)

AF:

0.467

AC:

7136

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

1780

AN:

3472

East Asian (EAS)

AF:

0.251

AC:

1297

AN:

5172

South Asian (SAS)

AF:

0.422

AC:

2030

AN:

4808

European-Finnish (FIN)

AF:

0.468

AC:

4943

AN:

10572

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.467

AC:

31717

AN:

67972

Other (OTH)

AF:

0.464

AC:

982

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2003

4006

6008

8011

10014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.466

Hom.:

77176

Bravo

AF:

0.469

TwinsUK

AF:

0.441

AC:

1635

ALSPAC

AF:

0.466

AC:

1797

ESP6500AA

AF:

0.510

AC:

2249

ESP6500EA

AF:

0.468

AC:

4028

ExAC

AF:

0.452

AC:

54869

Asia WGS

AF:

0.408

AC:

1417

AN:

3478

EpiCase

AF:

0.465

EpiControl

AF:

0.464

ClinVar

Significance: Benign

Submissions summary: Benign:7

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 14, 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 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Respiratory papillomatosis, juvenile recurrent, congenital

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammation with arthritis and dyskeratosis

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.0035

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00088

LIST_S2

Benign

0.48

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

MetaRNN

Benign

0.00031

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

MetaSVM

Benign

-0.94

PhyloP100

0.55

PrimateAI

Benign

0.37

PROVEAN

Benign

1.8

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

REVEL

Benign

0.071

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.055

MPC

0.21

ClinPred

0.0020

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.035

gMVP

0.31

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

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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