1-247424386-A-G

Position:

chr1-247424386-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1PP2BP4_ModerateBS1BS2

The NM_001243133.2(NLRP3):c.937A>G(p.Ile313Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I313T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4O:1

Conservation

PhyloP100: 0.0790

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 -7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001243133.2

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLRP3. . Gene score misZ 2.1417 (greater than the threshold 3.09). Trascript score misZ 3.5037 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.075436145).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000196 (287/1461874) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 140 alleles in male gnomad4_exome subpopulation. Median coverage is 43. This position pass quality control queck.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2 linkuse as main transcript	c.937A>G	p.Ile313Val	missense_variant	4/10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 linkuse as main transcript	c.937A>G	p.Ile313Val	missense_variant	4/10	1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

250946

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000468

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000196

AC:

287

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000138

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2022	Identified in additional patients with suspected CAPS or systemic auto-inflammatory disorders in published literature, although detailed clinical information is not available (Cuisset et al., 2011; Rusmini et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(I313V); This variant is associated with the following publications: (PMID: 32082075, 32199921, 34426522, 28814775, 19302049, 21109514, 26386126, 27191192) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 13, 2018	Variant classified as Uncertain Significance - Favor Benign. The p.Ile315Val var iant in NLRP3 has been reported (as p.Ile313Val) in 1 individual with CAPS, and segregated with disease in at least 3 affected family members (Cuisset 2011). It was also reported in one individual with mevalonate kinase deficiency who carri ed additional variants in the MKV gene that were sufficient to explain their phe notype (Rusmini 2016). This variant has also been identified in 0.05% (58/126272 ) of European chromosomes by the Genome Aggregation Database (gnomAD; http://gno mad.broadinstitute.org/). Computational prediction tools and conservation analys is suggest that an isoleucine to valine change at position 315 may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. On the other hand, additional computational tools suggest that this varia nt may create a novel splice site; however, this prediction may not reflect biol ogical function. In summary, while its frequency suggests that it is more likely to be benign, the clinical significance of the p.Ile315Val variant is uncertain due to the presence of conflicting data. ACMG/AMP Criteria applied: BS1, PP1. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2019	The NLRP3 c.943A>G; p.Ile315Val variant (rs180177501) is reported in the medical literature in individuals with cryopyrin-associated periodic syndrome and segregating with disease in at least one family (Cuisset 2011, Rusmini 2016). The variant is reported in the ClinVar database as a variant of uncertain significance (Variation ID: 97989) and an expert panel considers this variant to be of uncertain significance (Van Gijn 2018). The variant is reported in the European (non-Finnish population) with an allele frequency of 0.05% (61/128760 alleles) in the Genome Aggregation Database. The isoleucine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predicts this variant is tolerated. However, most known pathogenic NLRP3 variants occur in this region (Masters 2009). Given the lack of clinical and functional data, the significance of the variant is uncertain at this time. References: Cuisset L et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011 Mar;70(3):495-9. Masters SL et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*).Annu Rev Immunol. 2009;27:621-68. Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537. -

Familial cold autoinflammatory syndrome 1

Benign:1Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2021

The c.943A>G (p.I315V) alteration is located in exon 3 (coding exon 3) of the NLRP3 gene. This alteration results from a A to G substitution at nucleotide position 943, causing the isoleucine (I) at amino acid position 315 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C1835697:Keratitis fugax hereditaria;C4521680:Hearing loss, autosomal dominant 34, with or without inflammation;C4551895:Familial cold autoinflammatory syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 05, 2024

- -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 12, 2021

- -

Cryopyrin associated periodic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Familial amyloid nephropathy with urticaria AND deafness

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. -

Chronic infantile neurological, cutaneous and articular syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.24

CADD

Benign

0.23

DANN

Benign

0.28

DEOGEN2

Benign

0.18

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

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.22

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

M_CAP

Benign

0.025

MetaRNN

Benign

0.075

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

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.52

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

REVEL

Uncertain

0.37

Sift

Benign

0.23

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

Sift4G

Benign

0.29

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

Polyphen

0.0030

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

Vest4

0.60

MVP

0.75

MPC

0.38

ClinPred

0.062

GERP RS

-4.5

Varity_R

0.045

gMVP

0.48

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