17-5521756-A-G

Position:

chr17-5521756-A-G

Variant summary

Our verdict is Benign. Variant got -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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 links:

NLRP1 (HGNC:):

NLRP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
NLRP1	NM_033004.4 linkuse as main transcript	c.3551T>C	p.Met1184Thr	missense_variant	13/17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6 linkuse as main transcript	c.3551T>C	p.Met1184Thr	missense_variant	13/17	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

GnomAD3 exomes

AF:

0.0383

AC:

9583

AN:

250332

Hom.:

1240

AF XY:

0.0296

AC XY:

4005

AN XY:

135334

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 SAS exome

AF:

0.00445

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

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.233

Gnomad4 ASJ exome

AF:

0.00150

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00443

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00601

Gnomad4 OTH exome

AF:

0.00923

GnomAD4 genome

AF:

0.0200

AC:

3042

AN:

152308

Hom.:

240

Cov.:

AF XY:

0.0223

AC XY:

1664

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00540

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00613

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.00695

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over