1-247424229-A-G

Variant names:

Variant summary

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

The NM_001243133.2(NLRP3):c.780A>G(p.Arg260Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 1,614,012 control chromosomes in the GnomAD database, including 727,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 65767 hom., cov: 30)

Exomes 𝑓: 0.95 ( 661478 hom. )

Consequence

NLRP3
NM_001243133.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0360

Publications

28 publications found

Variant links:

Genes affected

NLRP3 (HGNC:16400): (NLR family pyrin domain containing 3) This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. The SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via the formation of ion channels in macrophages. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), keratoendotheliitis fugax hereditarian, and deafness, autosomal dominant 34, with or without inflammation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Aug 2020]

NLRP3 Gene-Disease associations (from GenCC):

CINCA syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
cryopyrin-associated periodic syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
familial cold autoinflammatory syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
familial cold autoinflammatory syndrome 1
Inheritance: AD Classification: STRONG Submitted by: G2P
Muckle-Wells syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
keratitis fugax hereditaria
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NLRP3 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=-0.61).

BP6

Variant 1-247424229-A-G is Benign according to our data. Variant chr1-247424229-A-G is described in ClinVar as Benign. ClinVar VariationId is 403243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.036 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.780A>G	p.Arg260Arg	synonymous_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.780A>G	p.Arg260Arg	synonymous_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes

AF:

0.929

AC:

141148

AN:

152016

Hom.:

65724

Cov.:

show subpopulations

Gnomad AFR

AF:

0.855

Gnomad AMI

AF:

0.960

Gnomad AMR

AF:

0.952

Gnomad ASJ

AF:

0.971

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.890

Gnomad FIN

AF:

0.955

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.958

Gnomad OTH

AF:

0.929

GnomAD2 exomes

AF:

0.946

AC:

237877

AN:

251380

AF XY:

0.944

show subpopulations

Gnomad AFR exome

AF:

0.848

Gnomad AMR exome

AF:

0.971

Gnomad ASJ exome

AF:

0.971

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.950

Gnomad NFE exome

AF:

0.958

Gnomad OTH exome

AF:

0.954

GnomAD4 exome

AF:

0.951

AC:

1390021

AN:

1461878

Hom.:

661478

Cov.:

AF XY:

0.949

AC XY:

690079

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.857

AC:

28689

AN:

33480

American (AMR)

AF:

0.968

AC:

43300

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.971

AC:

25379

AN:

26136

East Asian (EAS)

AF:

0.999

AC:

39679

AN:

39700

South Asian (SAS)

AF:

0.878

AC:

75722

AN:

86258

European-Finnish (FIN)

AF:

0.952

AC:

50859

AN:

53414

Middle Eastern (MID)

AF:

0.939

AC:

5419

AN:

5768

European-Non Finnish (NFE)

AF:

0.956

AC:

1063596

AN:

1112004

Other (OTH)

AF:

0.950

AC:

57378

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4499

8998

13496

17995

22494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21616

43232

64848

86464

108080

<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:

0.928

AC:

141248

AN:

152134

Hom.:

65767

Cov.:

AF XY:

0.928

AC XY:

69027

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.855

AC:

35474

AN:

41484

American (AMR)

AF:

0.952

AC:

14563

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.971

AC:

3372

AN:

3472

East Asian (EAS)

AF:

0.997

AC:

5137

AN:

5150

South Asian (SAS)

AF:

0.890

AC:

4281

AN:

4810

European-Finnish (FIN)

AF:

0.955

AC:

10109

AN:

10590

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.958

AC:

65190

AN:

68022

Other (OTH)

AF:

0.929

AC:

1963

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

500

1000

1501

2001

2501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.949

Hom.:

103748

Bravo

AF:

0.927

Asia WGS

AF:

0.947

AC:

3296

AN:

3478

EpiCase

AF:

0.958

EpiControl

AF:

0.955

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary 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 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial cold autoinflammatory syndrome 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cryopyrin associated periodic syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial amyloid nephropathy with urticaria AND deafness

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Keratitis fugax hereditaria

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Chronic infantile neurological, cutaneous and articular syndrome

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

-0.61

CADD

Benign

3.1

(source)

DANN

Benign

0.47

PhyloP100

-0.036

Mutation Taster

=99/1

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