NM_001243133.2:c.2664-1675C>T

Variant names:

• chr1-247442297-C-T
• rs10157379
• NM_001243133.2:c.2664-1675C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243133.2(NLRP3):​c.2664-1675C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 151,998 control chromosomes in the GnomAD database, including 27,945 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (27945 hom., cov: 32)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.241
• Publications: 24 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

ENSG00000302155 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

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.2664-1675C>T		intron	N/A	NP_001230062.1
	NLRP3	NM_004895.5		c.2670-1675C>T		intron	N/A	NP_004886.3
	NLRP3	NM_001079821.3		c.2664-1675C>T		intron	N/A	NP_001073289.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.2664-1675C>T		intron	N/A	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.2664-1675C>T		intron	N/A	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.2493-1675C>T		intron	N/A	ENSP00000355452.3

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91928 AN: 151880 Hom.: 27919 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.596

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.605 AC: 91999 AN: 151998 Hom.: 27945 Cov.: 32 AF XY: 0.605 AC XY: 44909 AN XY: 74274

African (AFR) AF: 0.580 AC: 24028 AN: 41430

American (AMR) AF: 0.614 AC: 9382 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1657 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3116 AN: 5158

South Asian (SAS) AF: 0.590 AC: 2847 AN: 4822

European-Finnish (FIN) AF: 0.618 AC: 6521 AN: 10546

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.624 AC: 42431 AN: 67986

Other (OTH) AF: 0.599 AC: 1263 AN: 2110

Alfa AF: 0.614 Hom.: 57397

Bravo AF: 0.605

Asia WGS AF: 0.617 AC: 2144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.70
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10157379; hg19: chr1-247605599;