1-247424106-C-T

Position:

chr1-247424106-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001243133.2(NLRP3):c.657C>T(p.Thr219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,613,902 control chromosomes in the GnomAD database, including 5,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1291 hom., cov: 31)

Exomes 𝑓: 0.065 ( 3886 hom. )

Consequence

NLRP3
NM_001243133.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -10.6

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-247424106-C-T is Benign according to our data. Variant chr1-247424106-C-T is described in ClinVar as [Benign]. Clinvar id is 259562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424106-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-10.6 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2 linkuse as main transcript	c.657C>T	p.Thr219=	synonymous_variant	4/10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 linkuse as main transcript	c.657C>T	p.Thr219=	synonymous_variant	4/10	1	NM_001243133.2	ENSP00000337383	P1

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16651

AN:

151920

Hom.:

1290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0920

Gnomad ASJ

AF:

0.0758

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.0528

Gnomad FIN

AF:

0.0880

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0579

Gnomad OTH

AF:

0.103

GnomAD3 exomes

AF:

0.0802

AC:

20156

AN:

251268

Hom.:

1098

AF XY:

0.0755

AC XY:

10254

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0847

Gnomad ASJ exome

AF:

0.0805

Gnomad EAS exome

AF:

0.143

Gnomad SAS exome

AF:

0.0451

Gnomad FIN exome

AF:

0.0870

Gnomad NFE exome

AF:

0.0573

Gnomad OTH exome

AF:

0.0779

GnomAD4 exome

AF:

0.0647

AC:

94567

AN:

1461864

Hom.:

3886

Cov.:

AF XY:

0.0639

AC XY:

46440

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.225

Gnomad4 AMR exome

AF:

0.0853

Gnomad4 ASJ exome

AF:

0.0801

Gnomad4 EAS exome

AF:

0.149

Gnomad4 SAS exome

AF:

0.0476

Gnomad4 FIN exome

AF:

0.0839

Gnomad4 NFE exome

AF:

0.0553

Gnomad4 OTH exome

AF:

0.0767

GnomAD4 genome

AF:

0.110

AC:

16670

AN:

152038

Hom.:

1291

Cov.:

AF XY:

0.111

AC XY:

8252

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.213

Gnomad4 AMR

AF:

0.0917

Gnomad4 ASJ

AF:

0.0758

Gnomad4 EAS

AF:

0.147

Gnomad4 SAS

AF:

0.0529

Gnomad4 FIN

AF:

0.0880

Gnomad4 NFE

AF:

0.0579

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.0674

Hom.:

939

Bravo

AF:

0.116

Asia WGS

AF:

0.0910

AC:

315

AN:

3478

EpiCase

AF:

0.0612

EpiControl

AF:

0.0606

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	p.Thr221Thr in exon 5 of the NLPR3 gene: This variant is not expected to have cl inical significance because it does not alter an amino acid residue and it has b een identified in 8% (23018/276946) of the total chromosomes by the the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7525979). -
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+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30246732, 30131971) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial cold autoinflammatory syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cryopyrin associated periodic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Familial amyloid nephropathy with urticaria AND deafness

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Chronic infantile neurological, cutaneous and articular syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.026

DANN

Benign

0.57

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