Genetic Variant NLRP3:p.Ala75Val (chr1-247419024-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001243133.2(NLRP3):c.224C>T(p.Ala75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A75E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

NLRP3
NM_001243133.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 1.15

Publications

14 publications found

Variant links:

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

NLRP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 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=0.115327865).

BP6

Variant 1-247419024-C-T is Benign according to our data. Variant chr1-247419024-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 234286.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000179 (261/1461386) while in subpopulation MID AF = 0.00381 (22/5768). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAdExome4. There are 117 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 21 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRP3	NM_001243133.2	MANE Select	c.224C>T	p.Ala75Val	missense	Exon 2 of 10	NP_001230062.1	A0A7I2R3P8
NLRP3	NM_004895.5		c.230C>T	p.Ala77Val	missense	Exon 2 of 10	NP_004886.3
NLRP3	NM_001079821.3		c.224C>T	p.Ala75Val	missense	Exon 3 of 11	NP_001073289.2	A0A7I2R3P8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRP3	ENST00000336119.8	TSL:1 MANE Select	c.224C>T	p.Ala75Val	missense	Exon 2 of 10	ENSP00000337383.4	A0A7I2R3P8
NLRP3	ENST00000391828.8	TSL:1	c.224C>T	p.Ala75Val	missense	Exon 3 of 11	ENSP00000375704.4	A0A7I2R3P8
NLRP3	ENST00000366496.7	TSL:1	c.224C>T	p.Ala75Val	missense	Exon 1 of 8	ENSP00000355452.3	A0A7I2PMC6

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

151572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

249554

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000179

AC:

261

AN:

1461386

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52946

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000167

AC:

186

AN:

1111986

Other (OTH)

AF:

0.000281

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

151692

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74096

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41276

American (AMR)

AF:

0.0000656

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Autoinflammatory syndrome (1)

Cryopyrin associated periodic syndrome (1)

Inborn genetic diseases (1)

NLRP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.068

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.046

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.95

PhyloP100

1.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

REVEL

Benign

0.10

Sift

Benign

0.034

Sift4G

Uncertain

0.045

Polyphen

0.94

Vest4

0.34

MVP

0.99

MPC

0.89

ClinPred

0.047

GERP RS

2.4

PromoterAI

-0.0034

Neutral

(source)

Varity_R

0.11

gMVP

0.49

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over