1-247419024-C-T

Variant names:

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, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome, cryopyrin-associated periodic 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2 link	c.224C>T	p.Ala75Val	missense_variant	Exon 2 of 10	ENST00000336119.8	NP_001230062.1	Q96P20A0A7I2R3P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8 link	c.224C>T	p.Ala75Val	missense_variant	Exon 2 of 10	1	NM_001243133.2	ENSP00000337383.4		A0A7I2R3P8

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jun 28, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala77Val variant in NLRP3 has not been previously reported in individuals with hearing loss or Cryopyrin-associated periodic syndromes, but has been identified in 0.01% (6/30606) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 234286). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4. -

Jan 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NLRP3 c.230C>T (p.Ala77Val) results in a non-conservative amino acid change located in the PAAD/DAPIN/Pyrin domain (IPR004020) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249554 control chromosomes. The observed variant frequency is approximately 185.93 fold of the estimated maximal expected allele frequency for a pathogenic variant in NLRP3 causing Cryopyrin Associated Periodic Syndrome phenotype (6.3e-07). c.230C>T has been reported in the literature in a heterozygous individual affected with Presumed Ocular Histoplasmosis Syndrome (Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Cryopyrin Associated Periodic Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32707200). ClinVar contains an entry for this variant (Variation ID: 234286). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:1Benign:1

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32707200) -

Inborn genetic diseases

Uncertain:1

Nov 20, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.230C>T (p.A77V) alteration is located in exon 1 (coding exon 1) of the NLRP3 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the alanine (A) at amino acid position 77 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NLRP3-related disorder

Uncertain:1

Jan 05, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NLRP3 c.230C>T variant is predicted to result in the amino acid substitution p.Ala77Val. This variant was reported in an individual with presumed ocular histoplasmosis syndrome (POHS, Li et al. 2020. PubMed ID: 32707200). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be causative of autosomal dominant disorders (http://gnomad.broadinstitute.org/variant/1-247582326-C-T). While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autoinflammatory syndrome

Uncertain:1

Apr 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cryopyrin associated periodic syndrome

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

.;T;T;.;.;.;.;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.068

LIST_S2

Uncertain

0.86

D;.;D;D;.;D;D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

1.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

N;N;N;N;N;.;.;N

REVEL

Benign

0.10

Sift

Benign

0.034

D;D;D;D;D;.;.;D

Sift4G

Uncertain

0.045

D;D;D;D;D;.;.;D

Polyphen

0.94

P;B;B;P;P;.;.;B

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over