1-247418307-C-CT

Variant names:

• chr1-247418307-C-CT
• rs144128307
• NM_001243133.2:c.-482dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.165
• Publications: 1 publications found

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: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cryopyrin-associated periodic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• familial cold autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• 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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.-482dupT		5_prime_UTR_variant	Exon 2 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.-482dupT		5_prime_UTR_variant	Exon 2 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes AF: 0.000595 AC: 88 AN: 147792 Hom.: 0 Cov.: 32

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.: 0 Cov.: 0 AF XY: 0.0611 AC XY: 1308 AN XY: 21422

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

African (AFR) AF: 0.0350 AC: 23 AN: 658

American (AMR) AF: 0.0989 AC: 263 AN: 2660

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 43 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: 74 AN: 1722

Middle Eastern (MID) AF: 0.0522 AC: 7 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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000602 AC: 89 AN: 147846 Hom.: 0 Cov.: 32 AF XY: 0.000639 AC XY: 46 AN XY: 71958

African (AFR) AF: 0.000295 AC: 12 AN: 40654

American (AMR) AF: 0.000135 AC: 2 AN: 14786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00550 AC: 28 AN: 5088

South Asian (SAS) AF: 0.000858 AC: 4 AN: 4662

European-Finnish (FIN) AF: 0.000838 AC: 8 AN: 9542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000496 AC: 33 AN: 66496

Other (OTH) AF: 0.000986 AC: 2 AN: 2028

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Familial amyloid nephropathy with urticaria AND deafness Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chronic infantile neurological, cutaneous and articular syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs144128307; hg19: chr1-247581609; COSMIC: COSV60221253; COSMIC: COSV60221253;