rs104895566

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_144687.4(NLRP12):c.1343G>C(p.Gly448Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,613,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 1 hom. )

Consequence

NLRP12
NM_144687.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.450

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_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18164584).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4 linkuse as main transcript	c.1343G>C	p.Gly448Ala	missense_variant	3/10	ENST00000324134.11	NP_653288.1	P59046-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NLRP12	ENST00000324134.11 linkuse as main transcript	c.1343G>C	p.Gly448Ala	missense_variant	3/10	1	NM_144687.4	ENSP00000319377.6	P59046-1
NLRP12	ENST00000345770.9 linkuse as main transcript	c.1343G>C	p.Gly448Ala	missense_variant	3/9	1		ENSP00000341428.5	A0A0C4DH17
NLRP12	ENST00000391772.1 linkuse as main transcript	c.1343G>C	p.Gly448Ala	missense_variant	3/7	1		ENSP00000375652.1	A0A0C4DFY3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250486

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000903

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2017	The G448A variant in the NLRP12 gene has been reported in an individual with late onset autoinflammatory disorder (Vitale et al., 2013). The G448A variant is observed in 7/65966 (0.011%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The G448A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G448A as a variant of uncertain significance, which may be related to the reported rash, migraine, and pain in this individual. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

Familial cold autoinflammatory syndrome 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	NLRP12 NM_144687 exon 3 p.Gly448Ala (c.1343G>C): This variant has not been reported in the literature but is present in 12/126260 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs104895566). This variant is present in ClinVar (Variation ID:97886). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 448 of the NLRP12 protein (p.Gly448Ala). This variant is present in population databases (rs104895566, gnomAD 0.01%). This missense change has been observed in individual(s) with chronic NLRP12-autoinflammatory disorder (PMID: 24064030). ClinVar contains an entry for this variant (Variation ID: 97886). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NLRP12 protein function with a negative predictive value of 80%. 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. -

NLRP12-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

The NLRP12 c.1343G>C variant is predicted to result in the amino acid substitution p.Gly448Ala. The variant has been reported in an individual with later onset, chronic NLRP12-autoinflammatory disorder, also known as familial cold autoinflammatory syndrome (Vitale et al. 2013. PubMed ID: 24064030). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.14

T;.;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.3

M;M;M;.;.

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Benign

0.24

Sift

Benign

0.049

D;D;D;D;D

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.15

MVP

0.84

MPC

0.18

ClinPred

0.14

GERP RS

3.4

Varity_R

0.13

gMVP

0.17

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