rs104895564

Positions:

• chr19-53810809-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_144687.4(NLRP12):​c.850C>T​(p.Arg284Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (1 hom.)
• Consequence: NLRP12 NM_144687.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:8 O:1
• Conservation: PhyloP100: -0.205

Genes affected

NLRP12 (HGNC:22938): (NLR family pyrin domain containing 12) This gene encodes a member of the CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminus leucine-rich repeat region, functions as an attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-53810809-G-A is Pathogenic according to our data. Variant chr19-53810809-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1596.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=8, Pathogenic=2}.
• BS2: High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.850C>T	p.Arg284Ter	stop_gained	3/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.850C>T	p.Arg284Ter	stop_gained	3/10	1	NM_144687.4	ENSP00000319377	P4

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251008 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135750

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000670 AC: 98 AN: 1461804 Hom.: 1 Cov.: 40 AF XY: 0.0000591 AC XY: 43 AN XY: 727208

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74446

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000941 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Pathogenic:1 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Arg284*) in the NLRP12 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NLRP12 cause disease. This variant is present in population databases (rs104895564, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of familial cold autoinflammatory syndrome (FCAS) (PMID: 18230725). ClinVar contains an entry for this variant (Variation ID: 1596). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NLRP12 function (PMID: 18230725, 21360512). 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. -
Pathogenic, flagged submission	literature only	OMIM	Feb 05, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Oct 13, 2024	This sequence change creates a premature translational stop signal (GRCh38; NM_001277126.2:c.850C>T:p.Arg284Ter) in the NLRP12 protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. ClinVar contains an entry for this variant (Variation ID: 1596). Observed in healthy adults individual for a dominant disorder. Functional studies have shown conflicting NFKB activation by this variant (PMID: 18230725, 21360512) Based on conflicting evidence or insufficient data to determine whether the variant is benign or pathogenic, the clinical significance of this alteration remains unclear. In summary, this variant meets our criteria for classification as of Unknown Clinical Significance based on the evidence outlined. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2019	The NLRP12 c.850C>T; p.Arg284Ter variant (rs104895564) is published in the medical literature in one family with a hereditary periodic fever syndrome (Jeru 2008, Jeru 2011), but has also been reported in a reportedly unaffected individual (Rodriguez-Flores 2014). The variant is reported in the ClinVar database (Variation ID: 1596) and in the African population with an allele frequency of 0.1% (34/24916 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional studies have shown conflicting NFKB activation by this variant (Borghini 2011, Jeru 2008). Although the physiological relevance of NLRP12 in periodic fever syndrome is certain, if disease is caused by loss-of-function variants remained to be determined (Tuncer 2014). Due to conflicting information, the clinical significance of this variant is uncertain. References: Borghini S et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 2011 Mar;63(3):830-9. Jeru I et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. Jeru I et al. Role of interleukin-1ß in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis Rheum. 2011 Jul;63(7):2142-8. Rodriguez-Flores JL et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014 Jan;35(1):105-16. Tuncer S et al. The multifaceted nature of NLRP12. J Leukoc Biol. 2014 Dec;96(6):991-1000. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 05, 2021	The inherited c.850C>T(p.Arg284Ter)stop-gained variant identified in exon 3(of 10) of the NLRP12 gene creates a premature translation termination codon and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, loss-of-function is not an established mechanism of disease for NLRP12 related disorder. The p.Arg284Ter variant has 0.0004403 allele frequency in the gnomAD(v3) database across all populations represented in the database (67 out of 152,152 heterozygous alleles, no homozygotes), and 0.001448 allele frequency in the African/African-American sub-population (60 out of 41,450 heterozygous alleles, no homozygotes). Although the variant has been reported in a family affected with hereditary periodic fever syndrome [PMID: 18230725], functional studies show contradictory data regarding potential pathogenicity of this variant [PMID: 18230725; PMID: 21360512]. Given the lack of compelling evidence for its pathogenicity, the inherited c.850C>T(p.Arg284Ter) stop-gained variant identified in the NLRP12geneis reported as a variant of uncertain significance. -

not provided Pathogenic:1 Uncertain:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2024	Reported in association with NLRP12-related familial cold autoinflammatory syndrome in the published literature (PMID: 18230725); Published functional studies demonstrate a damaging effect (PMID: 18230725); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34054914, 25525159, 21480187, 31589614, 32743516, 33525590, 30559449, 24906912, 31820221, 28421071, 27314497, 24123366, 20007570, 21360512, 18230725, 31345219, 30788684) -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 15, 2024	BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.052	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
Vest4		0.55
GERP RS		-0.47

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: rs104895564; hg19: chr19-54314063; COSMIC: COSV60748927; COSMIC: COSV60748927;