NM_001243133.2:c.1231C>T

Variant names:

• chr1-247424680-C-T
• rs148478875
• NM_001243133.2:c.1231C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001243133.2(NLRP3):​c.1231C>T​(p.Leu411Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00866 in 1,614,230 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (65 hom.)
• Consequence: NLRP3 NM_001243133.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.698
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-247424680-C-T is Benign according to our data. Variant chr1-247424680-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.698 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00622 (947/152346) while in subpopulation NFE AF = 0.00911 (620/68026). AF 95% confidence interval is 0.00852. There are 6 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 947 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.1231C>T	p.Leu411Leu	synonymous	Exon 4 of 10	NP_001230062.1
	NLRP3	NM_004895.5		c.1237C>T	p.Leu413Leu	synonymous	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.1231C>T	p.Leu411Leu	synonymous	Exon 5 of 11	NP_001073289.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.1231C>T	p.Leu411Leu	synonymous	Exon 4 of 10	ENSP00000337383.4
	NLRP3	ENST00000391828.8	TSL:1	c.1231C>T	p.Leu411Leu	synonymous	Exon 5 of 11	ENSP00000375704.4
	NLRP3	ENST00000366496.7	TSL:1	c.1231C>T	p.Leu411Leu	synonymous	Exon 3 of 8	ENSP00000355452.3

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 947 AN: 152228 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00609 AC: 1531 AN: 251362 AF XY: 0.00648

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00939

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00891 AC: 13030 AN: 1461884 Hom.: 65 Cov.: 42 AF XY: 0.00879 AC XY: 6392 AN XY: 727246

African (AFR) AF: 0.00179 AC: 60 AN: 33480

American (AMR) AF: 0.00360 AC: 161 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86258

European-Finnish (FIN) AF: 0.0111 AC: 594 AN: 53414

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0105 AC: 11729 AN: 1112012

Other (OTH) AF: 0.00545 AC: 329 AN: 60392

GnomAD4 genome AF: 0.00622 AC: 947 AN: 152346 Hom.: 6 Cov.: 32 AF XY: 0.00613 AC XY: 457 AN XY: 74500

African (AFR) AF: 0.00178 AC: 74 AN: 41582

American (AMR) AF: 0.00732 AC: 112 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00911 AC: 620 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00788 Hom.: 4

Bravo AF: 0.00558

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00848

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	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 (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.1
DANN	Benign	0.75
PhyloP100		-0.70
Mutation Taster		=98/2	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: rs148478875; hg19: chr1-247587982; COSMIC: COSV60223527;