rs61841189

Variant names:

• chr1-247444846-C-T
• rs61841189
• NM_001243133.2:c.3005+25C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001243133.2(NLRP3):​c.3005+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,611,542 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (59 hom.)
• Consequence: NLRP3 NM_001243133.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.29
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-247444846-C-T is Benign according to our data. Variant chr1-247444846-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00652 (993/152264) while in subpopulation NFE AF = 0.0111 (755/68004). AF 95% confidence interval is 0.0104. There are 5 homozygotes in GnomAd4. There are 436 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 993 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	NM_001243133.2	MANE Select	c.3005+25C>T		intron	N/A	NP_001230062.1	A0A7I2R3P8
	NLRP3	NM_004895.5		c.3011+25C>T		intron	N/A	NP_004886.3
	NLRP3	NM_001079821.3		c.3005+25C>T		intron	N/A	NP_001073289.2	A0A7I2R3P8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.3005+25C>T		intron	N/A	ENSP00000337383.4	A0A7I2R3P8
	NLRP3	ENST00000391828.8	TSL:1	c.3005+25C>T		intron	N/A	ENSP00000375704.4	A0A7I2R3P8
	NLRP3	ENST00000366496.7	TSL:1	c.2834+25C>T		intron	N/A	ENSP00000355452.3	A0A7I2PMC6

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 994 AN: 152146 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00518 AC: 1291 AN: 249274 AF XY: 0.00476

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.000791

Gnomad NFE exome AF: 0.00852

Gnomad OTH exome AF: 0.00672

GnomAD4 exome AF: 0.00763 AC: 11141 AN: 1459278 Hom.: 59 Cov.: 31 AF XY: 0.00732 AC XY: 5318 AN XY: 726012

African (AFR) AF: 0.00138 AC: 46 AN: 33426

American (AMR) AF: 0.00726 AC: 324 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86070

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53378

Middle Eastern (MID) AF: 0.000800 AC: 4 AN: 5002

European-Non Finnish (NFE) AF: 0.00923 AC: 10253 AN: 1110730

Other (OTH) AF: 0.00732 AC: 441 AN: 60230

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152264 Hom.: 5 Cov.: 32 AF XY: 0.00586 AC XY: 436 AN XY: 74458

African (AFR) AF: 0.00135 AC: 56 AN: 41568

American (AMR) AF: 0.0101 AC: 154 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 755 AN: 68004

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00789 Hom.: 0

Bravo AF: 0.00660

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cryopyrin associated periodic syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0050
DANN	Benign	0.50
PhyloP100		-2.3
Mutation Taster		=99/1	polymorphism

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: rs61841189; hg19: chr1-247608148;