chr1-247418240-T-G

Position:

chr1-247418240-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001243133.2(NLRP3):c.-561T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 162,406 control chromosomes in the GnomAD database, including 933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 878 hom., cov: 32)

Exomes 𝑓: 0.077 ( 55 hom. )

Consequence

NLRP3
NM_001243133.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.492

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 1-247418240-T-G is Benign according to our data. Variant chr1-247418240-T-G is described in ClinVar as [Benign]. Clinvar id is 296926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247418240-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2 linkuse as main transcript	c.-561T>G		5_prime_UTR_variant	2/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8 linkuse as main transcript	c.-561T>G		5_prime_UTR_variant	2/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15524

AN:

152164

Hom.:

879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0985

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.0749

Gnomad EAS

AF:

0.00384

Gnomad SAS

AF:

0.0531

Gnomad FIN

AF:

0.0747

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.111

GnomAD4 exome

AF:

0.0773

AC:

783

AN:

10124

Hom.:

Cov.:

AF XY:

0.0730

AC XY:

387

AN XY:

5300

show subpopulations

Gnomad4 AFR exome

AF:

0.0588

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.109

Gnomad4 EAS exome

AF:

0.0231

Gnomad4 SAS exome

AF:

0.0340

Gnomad4 FIN exome

AF:

0.0500

Gnomad4 NFE exome

AF:

0.0845

Gnomad4 OTH exome

AF:

0.0526

GnomAD4 genome

AF:

0.102

AC:

15533

AN:

152282

Hom.:

878

Cov.:

AF XY:

0.0993

AC XY:

7393

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0985

Gnomad4 AMR

AF:

0.160

Gnomad4 ASJ

AF:

0.0749

Gnomad4 EAS

AF:

0.00385

Gnomad4 SAS

AF:

0.0532

Gnomad4 FIN

AF:

0.0747

Gnomad4 NFE

AF:

0.107

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.103

Hom.:

200

Bravo

AF:

0.110

Asia WGS

AF:

0.0430

AC:

151

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

-0.72

CADD

Benign

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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