1-247418307-CTTT-CTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001243133.2(NLRP3):c.-482dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 188,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.060 ( 0 hom. )

Consequence

NLRP3
NM_001243133.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 0.165

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

CINCA syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
cryopyrin-associated periodic syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
familial cold autoinflammatory syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
familial cold autoinflammatory syndrome 1
Inheritance: AD Classification: STRONG Submitted by: G2P
Muckle-Wells syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
keratitis fugax hereditaria
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NLRP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000602 (89/147846) while in subpopulation EAS AF = 0.0055 (28/5088). AF 95% confidence interval is 0.00391. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 89 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243133.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NLRP3	NM_001243133.2	MANE Select	c.-482dupT	5_prime_UTR	Exon 2 of 10	NP_001230062.1	A0A7I2R3P8
NLRP3	NM_004895.5		c.-476dupT	5_prime_UTR	Exon 2 of 10	NP_004886.3
NLRP3	NM_001127461.3		c.-482dupT	5_prime_UTR	Exon 2 of 9	NP_001120933.2	A0A7I2PMC6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.-482dupT	5_prime_UTR	Exon 2 of 10	ENSP00000337383.4	A0A7I2R3P8
NLRP3	ENST00000366496.7	TSL:1	c.-482dupT	5_prime_UTR	Exon 1 of 8	ENSP00000355452.3	A0A7I2PMC6
NLRP3	ENST00000391827.3	TSL:1	c.-482dupT	5_prime_UTR	Exon 2 of 9	ENSP00000375703.3	A0A7I2PRX0

Frequencies

GnomAD3 genomes

AF:

0.000595

AC:

AN:

147792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00549

Gnomad SAS

AF:

0.000641

Gnomad FIN

AF:

0.000838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000496

Gnomad OTH

AF:

0.000993

GnomAD4 exome

AF:

0.0597

AC:

2426

AN:

40606

Hom.:

Cov.:

AF XY:

0.0611

AC XY:

1308

AN XY:

21422

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0350

AC:

AN:

658

American (AMR)

AF:

0.0989

AC:

263

AN:

2660

Ashkenazi Jewish (ASJ)

AF:

0.0566

AC:

AN:

760

East Asian (EAS)

AF:

0.0695

AC:

144

AN:

2072

South Asian (SAS)

AF:

0.0660

AC:

450

AN:

6816

European-Finnish (FIN)

AF:

0.0430

AC:

AN:

1722

Middle Eastern (MID)

AF:

0.0522

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0549

AC:

1305

AN:

23754

Other (OTH)

AF:

0.0576

AC:

117

AN:

2030

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

224

448

671

895

1119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000602

AC:

AN:

147846

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

AN XY:

71958

show subpopulations

African (AFR)

AF:

0.000295

AC:

AN:

40654

American (AMR)

AF:

0.000135

AC:

AN:

14786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00550

AC:

AN:

5088

South Asian (SAS)

AF:

0.000858

AC:

AN:

4662

European-Finnish (FIN)

AF:

0.000838

AC:

AN:

9542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000496

AC:

AN:

66496

Other (OTH)

AF:

0.000986

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chronic infantile neurological, cutaneous and articular syndrome (1)

Familial amyloid nephropathy with urticaria AND deafness (1)

Familial cold autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.17

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over