rs61841189

Positions:

chr1-247444846-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001243133.2(NLRP3):c.3005+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,611,542 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 59 hom. )

Consequence

NLRP3
NM_001243133.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.29

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:

NLRP3 (HGNC:):

NLRP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-247444846-C-T is Benign according to our data. Variant chr1-247444846-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 403244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247444846-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00652 (993/152264) while in subpopulation NFE AF= 0.0111 (755/68004). AF 95% confidence interval is 0.0104. There are 5 homozygotes in gnomad4. There are 436 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2 linkuse as main transcript	c.3005+25C>T		intron_variant		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.3005+25C>T		intron_variant		1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

Frequencies

GnomAD3 genomes

AF:

0.00653

AC:

994

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00518

AC:

1291

AN:

249274

Hom.:

AF XY:

0.00476

AC XY:

642

AN XY:

134960

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.000791

Gnomad NFE exome

AF:

0.00852

Gnomad OTH exome

AF:

0.00672

GnomAD4 exome

AF:

0.00763

AC:

11141

AN:

1459278

Hom.:

Cov.:

AF XY:

0.00732

AC XY:

5318

AN XY:

726012

show subpopulations

Gnomad4 AFR exome

AF:

0.00138

Gnomad4 AMR exome

AF:

0.00726

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.00923

Gnomad4 OTH exome

AF:

0.00732

GnomAD4 genome

AF:

0.00652

AC:

993

AN:

152264

Hom.:

Cov.:

AF XY:

0.00586

AC XY:

436

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00789

Hom.:

Bravo

AF:

0.00660

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NLRP3: BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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: High allele frequency -

Cryopyrin associated periodic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.0050

DANN

Benign

0.50

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