NM_001243133.2:c.592G>A

Variant names:

• chr1-247424041-G-A
• rs121908147
• NM_001243133.2:c.592G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001243133.2(NLRP3):​c.592G>A​(p.Val198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,614,016 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V198L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0085 (62 hom.)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:10 O:2
• Conservation: PhyloP100: -0.254
• Publications: 110 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 -12 ACMG points.

• PP2: Missense variant in the NLRP3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.1417 (below the threshold of 3.09). Trascript score misZ: 3.5037 (above the threshold of 3.09). GenCC associations: The gene is linked to CINCA syndrome, familial cold autoinflammatory syndrome, cryopyrin-associated periodic syndrome, familial cold autoinflammatory syndrome 1, Muckle-Wells syndrome, keratitis fugax hereditaria.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03694403).
• BP6: Variant 1-247424041-G-A is Benign according to our data. Variant chr1-247424041-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4371.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00726 (1104/152162) while in subpopulation NFE AF = 0.00866 (589/68004). AF 95% confidence interval is 0.00808. There are 10 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1104 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.592G>A	p.Val198Met	missense	Exon 4 of 10	NP_001230062.1	A0A7I2R3P8
	NLRP3	NM_004895.5		c.598G>A	p.Val200Met	missense	Exon 4 of 10	NP_004886.3
	NLRP3	NM_001079821.3		c.592G>A	p.Val198Met	missense	Exon 5 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.592G>A	p.Val198Met	missense	Exon 4 of 10	ENSP00000337383.4	A0A7I2R3P8
	NLRP3	ENST00000391828.8	TSL:1	c.592G>A	p.Val198Met	missense	Exon 5 of 11	ENSP00000375704.4	A0A7I2R3P8
	NLRP3	ENST00000366496.7	TSL:1	c.592G>A	p.Val198Met	missense	Exon 3 of 8	ENSP00000355452.3	A0A7I2PMC6

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1104 AN: 152044 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00541

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00832 AC: 2089 AN: 251192 AF XY: 0.00851

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.00928

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00853 AC: 12464 AN: 1461854 Hom.: 62 Cov.: 31 AF XY: 0.00846 AC XY: 6153 AN XY: 727226

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00416 AC: 186 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 301 AN: 26132

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

South Asian (SAS) AF: 0.00630 AC: 543 AN: 86254

European-Finnish (FIN) AF: 0.0238 AC: 1269 AN: 53414

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.00866 AC: 9626 AN: 1111996

Other (OTH) AF: 0.00782 AC: 472 AN: 60394

GnomAD4 genome AF: 0.00726 AC: 1104 AN: 152162 Hom.: 10 Cov.: 31 AF XY: 0.00789 AC XY: 587 AN XY: 74370

African (AFR) AF: 0.00130 AC: 54 AN: 41512

American (AMR) AF: 0.00661 AC: 101 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00541 AC: 26 AN: 4804

European-Finnish (FIN) AF: 0.0255 AC: 270 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00866 AC: 589 AN: 68004

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00757 Hom.: 15

Bravo AF: 0.00567

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00823 AC: 999

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
1	-	2	Familial cold autoinflammatory syndrome 1 (4)
-	1	1	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;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C1835697:Keratitis fugax hereditaria;C4521680:Hearing loss, autosomal dominant 34, with or without inflammation;C4551895:Familial cold autoinflammatory syndrome 1 (1)
-	1	-	Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C4551895:Familial cold autoinflammatory syndrome 1 (2)
-	-	1	Familial cold autoinflammatory syndrome (1)
-	-	1	Hearing loss, autosomal dominant 34, with or without inflammation (1)
-	1	-	Kidney disorder (1)
-	-	1	NLRP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.43
DANN	Benign	0.73
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.73	T
PhyloP100		-0.25
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.22
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.069	B
Vest4		0.070
MVP		0.51
MPC		0.46
ClinPred		0.0057	T
GERP RS		-7.4
Varity_R		0.039
gMVP		0.23
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: rs121908147; hg19: chr1-247587343; COSMIC: COSV60225809;