rs104895564

Positions:

chr19-53810809-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1PP5_StrongBS2

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 Uncertain significance (★★). 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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:5O:1

Conservation

PhyloP100: -0.205

Variant links:

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]

NLRP12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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 [Uncertain_significance]. Clinvar id is 1596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=5, not_provided=1}.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4 linkuse as main transcript	c.850C>T	p.Arg284Ter	stop_gained	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11 linkuse as main transcript	c.850C>T	p.Arg284Ter	stop_gained	3/10	1	NM_144687.4	P4	P59046-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

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:

AN:

251008

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135750

show subpopulations

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:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727208

show subpopulations

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:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74446

show subpopulations

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.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Pathogenic:1Uncertain:4

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. -
Pathogenic, flagged submission	literature only	OMIM	Feb 05, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -
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-1ÃŸ 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	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -

not provided

Pathogenic:1Other:1

Pathogenic, flagged submission	clinical testing	GeneDx	Feb 07, 2023	Reported in association with NLRP12-related familial cold autoinflammatory syndrome in the published literature (Jeru et al., 2008); 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; Published functional studies demonstrate a damaging effect (Jeru et al., 2008); This variant is associated with the following publications: (PMID: 34054914, 25525159, 21480187, 31589614, 30788684, 32743516, 33525590, 30559449, 24906912, 31820221, 28421071, 27314497, 24123366, 20007570, 21360512, 18230725) -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

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

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.052

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over