1-247418307-CTTT-CTTTTTTT

Variant names:

• chr1-247418307-C-CTTTT
• rs144128307
• NM_001243133.2:c.-485_-482dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001243133.2(NLRP3):​c.-485_-482dupTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 41,582 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: NLRP3 NM_001243133.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.165
• Publications: 0 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	NM_001243133.2	MANE Select	c.-485_-482dupTTTT		5_prime_UTR	Exon 2 of 10	NP_001230062.1	A0A7I2R3P8
	NLRP3	NM_004895.5		c.-479_-476dupTTTT		5_prime_UTR	Exon 2 of 10	NP_004886.3
	NLRP3	NM_001127461.3		c.-485_-482dupTTTT		5_prime_UTR	Exon 2 of 9	NP_001120933.2	A0A7I2PMC6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.-485_-482dupTTTT		5_prime_UTR	Exon 2 of 10	ENSP00000337383.4	A0A7I2R3P8
	NLRP3	ENST00000366496.7	TSL:1	c.-485_-482dupTTTT		5_prime_UTR	Exon 1 of 8	ENSP00000355452.3	A0A7I2PMC6
	NLRP3	ENST00000391827.3	TSL:1	c.-485_-482dupTTTT		5_prime_UTR	Exon 2 of 9	ENSP00000375703.3	A0A7I2PRX0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000240 AC: 1 AN: 41582 Hom.: 0 Cov.: 0 AF XY: 0.0000456 AC XY: 1 AN XY: 21938

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

African (AFR) AF: 0.00 AC: 0 AN: 668

American (AMR) AF: 0.00 AC: 0 AN: 2788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 766

East Asian (EAS) AF: 0.00 AC: 0 AN: 2134

South Asian (SAS) AF: 0.000143 AC: 1 AN: 6974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24304

Other (OTH) AF: 0.00 AC: 0 AN: 2072

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144128307; hg19: chr1-247581609;