1-247448734-G-C

Variant names:

• chr1-247448734-G-C
• rs10754558
• NM_001243133.2:c.*230G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001243133.2(NLRP3):​c.*230G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 583,860 control chromosomes in the GnomAD database, including 108,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31464 hom., cov: 32)
  • Exomes 𝑓: 0.59 (77133 hom.)
• Consequence: NLRP3 NM_001243133.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.286
• Publications: 215 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-247448734-G-C is Benign according to our data. Variant chr1-247448734-G-C is described in ClinVar as Benign. ClinVar VariationId is 296956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 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.*230G>C		3_prime_UTR	Exon 10 of 10	NP_001230062.1	A0A7I2R3P8
	NLRP3	NM_004895.5		c.*230G>C		3_prime_UTR	Exon 10 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.*230G>C		3_prime_UTR	Exon 11 of 11	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.*230G>C		3_prime_UTR	Exon 10 of 10	ENSP00000337383.4	A0A7I2R3P8
	NLRP3	ENST00000391828.8	TSL:1	c.*230G>C		3_prime_UTR	Exon 11 of 11	ENSP00000375704.4	A0A7I2R3P8
	NLRP3	ENST00000366496.7	TSL:1	c.*230G>C		3_prime_UTR	Exon 8 of 8	ENSP00000355452.3	A0A7I2PMC6

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96623 AN: 152016 Hom.: 31418 Cov.: 32

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.610

GnomAD4 exome AF: 0.594 AC: 256437 AN: 431726 Hom.: 77133 Cov.: 2 AF XY: 0.594 AC XY: 136612 AN XY: 229814

African (AFR) AF: 0.740 AC: 8984 AN: 12134

American (AMR) AF: 0.758 AC: 15318 AN: 20212

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 5744 AN: 13226

East Asian (EAS) AF: 0.584 AC: 16897 AN: 28948

South Asian (SAS) AF: 0.608 AC: 29029 AN: 47728

European-Finnish (FIN) AF: 0.571 AC: 15268 AN: 26762

Middle Eastern (MID) AF: 0.488 AC: 905 AN: 1854

European-Non Finnish (NFE) AF: 0.585 AC: 149957 AN: 256278

Other (OTH) AF: 0.583 AC: 14335 AN: 24584

GnomAD4 genome AF: 0.636 AC: 96729 AN: 152134 Hom.: 31464 Cov.: 32 AF XY: 0.636 AC XY: 47316 AN XY: 74360

African (AFR) AF: 0.743 AC: 30852 AN: 41498

American (AMR) AF: 0.711 AC: 10873 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1463 AN: 3470

East Asian (EAS) AF: 0.586 AC: 3030 AN: 5172

South Asian (SAS) AF: 0.611 AC: 2950 AN: 4826

European-Finnish (FIN) AF: 0.573 AC: 6060 AN: 10574

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39734 AN: 67988

Other (OTH) AF: 0.612 AC: 1292 AN: 2110

Alfa AF: 0.615 Hom.: 3629

Bravo AF: 0.648

Asia WGS AF: 0.630 AC: 2193 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Chronic infantile neurological, cutaneous and articular syndrome (1)
-	-	1	Cryopyrin associated periodic syndrome (1)
-	-	1	Familial amyloid nephropathy with urticaria AND deafness (1)
-	-	1	Familial cold autoinflammatory syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.41
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs10754558; hg19: chr1-247612036; COSMIC: COSV59510002; COSMIC: COSV59510002;