17-5583844-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_033004.4(NLRP1):c.114G>C(p.Ser38Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,569,478 control chromosomes in the GnomAD database, including 37,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 3465 hom., cov: 33)

Exomes 𝑓: 0.20 ( 34038 hom. )

Consequence

NLRP1
NM_033004.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -5.04

Publications

22 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-5583844-C-G is Benign according to our data. Variant chr17-5583844-C-G is described in ClinVar as [Benign]. Clinvar id is 403241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4 link	c.114G>C	p.Ser38Ser	synonymous_variant	Exon 1 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.114G>C	p.Ser38Ser	synonymous_variant	Exon 1 of 17	1	NM_033004.4	ENSP00000460475.1		Q9C000-1

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25905

AN:

152078

Hom.:

3472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0428

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.233

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.247

AC:

45290

AN:

183436

AF XY:

0.254

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.225

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.671

Gnomad FIN exome

AF:

0.251

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.198

AC:

280278

AN:

1417280

Hom.:

34038

Cov.:

AF XY:

0.203

AC XY:

142319

AN XY:

701002

show subpopulations

African (AFR)

AF:

0.0353

AC:

1154

AN:

32664

American (AMR)

AF:

0.225

AC:

8635

AN:

38448

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

5880

AN:

25414

East Asian (EAS)

AF:

0.620

AC:

23231

AN:

37450

South Asian (SAS)

AF:

0.376

AC:

30468

AN:

81076

European-Finnish (FIN)

AF:

0.240

AC:

12100

AN:

50356

Middle Eastern (MID)

AF:

0.208

AC:

1183

AN:

5694

European-Non Finnish (NFE)

AF:

0.170

AC:

185035

AN:

1087534

Other (OTH)

AF:

0.215

AC:

12592

AN:

58644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

13558

27117

40675

54234

67792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6936

13872

20808

27744

34680

<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:

0.170

AC:

25889

AN:

152198

Hom.:

3465

Cov.:

AF XY:

0.181

AC XY:

13482

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0426

AC:

1772

AN:

41560

American (AMR)

AF:

0.195

AC:

2983

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

807

AN:

3470

East Asian (EAS)

AF:

0.671

AC:

3459

AN:

5156

South Asian (SAS)

AF:

0.386

AC:

1860

AN:

4816

European-Finnish (FIN)

AF:

0.251

AC:

2654

AN:

10594

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.172

AC:

11699

AN:

67982

Other (OTH)

AF:

0.190

AC:

401

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

996

1991

2987

3982

4978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.146

Hom.:

627

Bravo

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

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 -

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

- -

NLRP1-related disorder

Benign:1

Jan 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.65

(source)

DANN

Benign

0.47

PhyloP100

-5.0

PromoterAI

0.20

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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