rs10754558

Positions:

• chr1-247448734-G-C
• chr1-247448734-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001243133.2(NLRP3):​c.*230G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 583,860 control chromosomes in the GnomAD database, including 108,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31464 hom., cov: 32)
  • Exomes 𝑓: 0.59 (77133 hom.)
• Consequence: NLRP3 NM_001243133.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.286

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-247448734-G-C is Benign according to our data. Variant chr1-247448734-G-C is described in ClinVar as [Benign]. Clinvar id is 296956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.*230G>C		3_prime_UTR_variant	10/10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.*230G>C		3_prime_UTR_variant	10/10	1	NM_001243133.2	ENSP00000337383	P1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96623 AN: 152016 Hom.: 31418 Cov.: 32

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.610

GnomAD4 exome AF: 0.594 AC: 256437 AN: 431726 Hom.: 77133 Cov.: 2 AF XY: 0.594 AC XY: 136612 AN XY: 229814

Gnomad4 AFR exome AF: 0.740

Gnomad4 AMR exome AF: 0.758

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.584

Gnomad4 SAS exome AF: 0.608

Gnomad4 FIN exome AF: 0.571

Gnomad4 NFE exome AF: 0.585

Gnomad4 OTH exome AF: 0.583

GnomAD4 genome AF: 0.636 AC: 96729 AN: 152134 Hom.: 31464 Cov.: 32 AF XY: 0.636 AC XY: 47316 AN XY: 74360

Gnomad4 AFR AF: 0.743

Gnomad4 AMR AF: 0.711

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.586

Gnomad4 SAS AF: 0.611

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.584

Gnomad4 OTH AF: 0.612

Alfa AF: 0.615 Hom.: 3629

Bravo AF: 0.648

Asia WGS AF: 0.630 AC: 2193 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cryopyrin associated periodic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Familial amyloid nephropathy with urticaria AND deafness Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Chronic infantile neurological, cutaneous and articular syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.41

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

LitVar

Other links and lift over

dbSNP: rs10754558; hg19: chr1-247612036; COSMIC: COSV59510002; COSMIC: COSV59510002;