1-247418258-A-T

Variant names:

• chr1-247418258-A-T
• rs116502550
• NM_001243133.2:c.-543A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001243133.2(NLRP3):​c.-543A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 176,730 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (0 hom.)
• Consequence: NLRP3 NM_001243133.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.237
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-247418258-A-T is Benign according to our data. Variant chr1-247418258-A-T is described in ClinVar as Benign. ClinVar VariationId is 296927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00685 (1035/151042) while in subpopulation NFE AF = 0.00847 (575/67852). AF 95% confidence interval is 0.0079. There are 13 homozygotes in GnomAd4. There are 569 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1035 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.-543A>T		5_prime_UTR	Exon 2 of 10	NP_001230062.1	A0A7I2R3P8
	NLRP3	NM_004895.5		c.-537A>T		5_prime_UTR	Exon 2 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.-77A>T		5_prime_UTR	Exon 2 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.-543A>T		5_prime_UTR	Exon 2 of 10	ENSP00000337383.4	A0A7I2R3P8
	NLRP3	ENST00000391828.8	TSL:1	c.-77A>T		5_prime_UTR	Exon 2 of 11	ENSP00000375704.4	A0A7I2R3P8
	NLRP3	ENST00000366496.7	TSL:1	c.-543A>T		5_prime_UTR	Exon 1 of 8	ENSP00000355452.3	A0A7I2PMC6

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1035 AN: 150990 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.00337

GnomAD4 exome AF: 0.00378 AC: 97 AN: 25688 Hom.: 0 Cov.: 0 AF XY: 0.00352 AC XY: 47 AN XY: 13356

African (AFR) AF: 0.00352 AC: 1 AN: 284

American (AMR) AF: 0.000688 AC: 2 AN: 2906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 346

East Asian (EAS) AF: 0.000683 AC: 1 AN: 1464

South Asian (SAS) AF: 0.000508 AC: 2 AN: 3940

European-Finnish (FIN) AF: 0.0124 AC: 11 AN: 884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.00531 AC: 77 AN: 14506

Other (OTH) AF: 0.00232 AC: 3 AN: 1292

GnomAD4 genome AF: 0.00685 AC: 1035 AN: 151042 Hom.: 13 Cov.: 32 AF XY: 0.00772 AC XY: 569 AN XY: 73672

African (AFR) AF: 0.000681 AC: 28 AN: 41104

American (AMR) AF: 0.00138 AC: 21 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000842 AC: 4 AN: 4752

European-Finnish (FIN) AF: 0.0380 AC: 389 AN: 10246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00847 AC: 575 AN: 67852

Other (OTH) AF: 0.00335 AC: 7 AN: 2088

Alfa AF: 0.0114 Hom.: 2

Bravo AF: 0.00345

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Chronic infantile neurological, cutaneous and articular syndrome (1)
-	-	1	Familial amyloid nephropathy with urticaria AND deafness (1)
-	-	1	Familial cold autoinflammatory syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.1
DANN	Benign	0.30
PhyloP100		0.24
PromoterAI		-0.0014	Neutral
Mutation Taster		=300/0	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: rs116502550; hg19: chr1-247581560;