chr1-247444061-G-A

Position:

• chr1-247444061-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1 PM2 PP2 PP5_Very_Strong BP4

The NM_001243133.2(NLRP3):​c.2753G>A​(p.Arg918Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 0.706

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]

LOC124904575 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a mutagenesis_site Decreased ability to activate the NLRP3 inflammasome. (size 0) in uniprot entity NLRP3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLRP3. . Gene score misZ 2.1417 (greater than the threshold 3.09). Trascript score misZ 3.5037 (greater than threshold 3.09). GenCC has associacion of gene with familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.
• PP5: Variant 1-247444061-G-A is Pathogenic according to our data. Variant chr1-247444061-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247444061-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.23971662). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.2753G>A	p.Arg918Gln	missense_variant	8/10	ENST00000336119.8	NP_001230062.1
LOC124904575	XR_007067005.1	n.144+4023C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.2753G>A	p.Arg918Gln	missense_variant	8/10	1	NM_001243133.2	ENSP00000337383	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NLRP3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a heterozygous change in affected family members from two families with sensorineural hearing loss with and without systemic autoinflammation (PMID: 28847925, 29342053). Functional studies in cultured patient cells showed release of high levels of IL-1β in response to stimulation with LPS, supporting gain of function mechanism of the c.2759G>A (p.Arg920Gln) variant (PMID: 28847925, 29342053). This variant is absent from the gnomAD population database and thus is presumed to be rare. In silico analyses do not support a deleterious effect of the c.2759G>A (p.Arg920Gln) variant on protein function. Based on the available evidence, the c.2759G>A (p.Arg920Gln) variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.R918Q; This variant is associated with the following publications: (PMID: 33329557, 34671876, Broderick2015[MeetingAbstract], 29342053, 28847925) -

Hearing loss, autosomal dominant 34, with or without inflammation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 28, 2017

- -

Cryopyrin associated periodic syndrome Uncertain:1

Uncertain significance, flagged submission

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces arginine with glutamine at codon 920 of the NLRP3 protein (p.Arg920Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate in families with cryopyrin-associated periodic syndromes (CAPS) and autosomal dominant deafness-34 (DFNA34) (PMID: 28847925). This variant is also known as p.Arg918Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 446409). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T;.;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.49	T;.;T;T;.;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.73	N;N;N;N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.077	T;T;T;T;T;.;T
Sift4G	Benign	0.16	T;T;T;T;T;.;T
Polyphen		0.059	B;B;B;B;B;.;B
Vest4		0.61
MutPred		0.54		.;Loss of methylation at R920 (P = 0.0393);Loss of methylation at R920 (P = 0.0393);.;.;.;.;
MVP		0.96
MPC		0.56
ClinPred		0.30	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1553293095; hg19: chr1-247607363; COSMIC: COSV60224775;