1-247425556-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BA1

The NM_001243133.2(NLRP3):c.2107C>A(p.Gln703Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,611,524 control chromosomes in the GnomAD database, including 1,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q703H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.033 ( 126 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1610 hom. )

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: -0.197

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in the NLRP3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.1417 (below the threshold of 3.09). Trascript score misZ: 3.5037 (above the threshold of 3.09). GenCC associations: The gene is linked to familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027211607).

BP6

Variant 1-247425556-C-A is Benign according to our data. Variant chr1-247425556-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259561.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=12}. Variant chr1-247425556-C-A is described in Lovd as [Benign]. Variant chr1-247425556-C-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.2107C>A	p.Gln703Lys	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.2107C>A	p.Gln703Lys	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

Frequencies

GnomAD3 genomes

AF:

0.0328

AC:

4990

AN:

152126

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00980

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.0678

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0356

Gnomad FIN

AF:

0.0475

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0466

Gnomad OTH

AF:

0.0387

GnomAD3 exomes

AF:

0.0391

AC:

9757

AN:

249326

Hom.:

238

AF XY:

0.0412

AC XY:

5564

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.00942

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0654

Gnomad EAS exome

AF:

0.00180

Gnomad SAS exome

AF:

0.0379

Gnomad FIN exome

AF:

0.0484

Gnomad NFE exome

AF:

0.0517

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0444

AC:

64760

AN:

1459280

Hom.:

1610

Cov.:

AF XY:

0.0444

AC XY:

32258

AN XY:

726112

show subpopulations

Gnomad4 AFR exome

AF:

0.00929

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0648

Gnomad4 EAS exome

AF:

0.00184

Gnomad4 SAS exome

AF:

0.0374

Gnomad4 FIN exome

AF:

0.0485

Gnomad4 NFE exome

AF:

0.0480

Gnomad4 OTH exome

AF:

0.0407

GnomAD4 genome

AF:

0.0328

AC:

4994

AN:

152244

Hom.:

126

Cov.:

AF XY:

0.0325

AC XY:

2417

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00987

Gnomad4 AMR

AF:

0.0235

Gnomad4 ASJ

AF:

0.0678

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0357

Gnomad4 FIN

AF:

0.0475

Gnomad4 NFE

AF:

0.0466

Gnomad4 OTH

AF:

0.0383

Alfa

AF:

0.0378

Hom.:

Bravo

AF:

0.0303

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0477

AC:

184

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0467

AC:

402

ExAC

AF:

0.0408

AC:

4957

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0510

EpiControl

AF:

0.0514

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 01, 2022	PS3, BS1, BP4 -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32477355, 26178285, 32199921, 22843550, 30245029, 29148409, 28638818, 28692792, 29977033, 29265930, 30140708, 29610014, 27576327, 29770580, 23215645, 29850521, 29230505, 22128899, 17509468, 22529966, 28028683, 26020059, 27036377, 27943647, 26848126, 27884173, 22403613, 22995991, 20182451, 25596455, 22935299, 18311798, 21245836, 19319132, 20981092, 29097263, 29500522, 30447690, 30536174) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 22, 2019	The p.Gln705Lys variant in NLRP3 is classified as benign because it has been identified in 3.8% (10781/280716) of total chromosomes, including 266 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been reported in association with autoimmune or inflammatory conditions, several studies have shown equal frequency in cases and ethnically matched controls (Jenko 2016, Lidar 2017, Naselli 2016, Yang 2017). ACMG/AMP criteria: BA1. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial cold autoinflammatory syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cryopyrin associated periodic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 02, 2022

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 10, 2022

- -

Familial amyloid nephropathy with urticaria AND deafness

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Chronic infantile neurological, cutaneous and articular syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.56

DANN

Benign

0.26

DEOGEN2

Benign

0.17

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.69

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

MetaRNN

Benign

0.0027

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

MetaSVM

Benign

-0.73

PrimateAI

Benign

0.26

PROVEAN

Benign

0.20

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

REVEL

Benign

0.16

Sift

Benign

0.23

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

Sift4G

Benign

0.58

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

Polyphen

0.14

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

Vest4

0.10

MPC

0.59

ClinPred

0.0028

GERP RS

-0.98

Varity_R

0.096

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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