rs764966959

chr19-53810550-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_144687.4(NLRP12):c.1109G>A(p.Arg370Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R370G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.890

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41982904).
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.1109G>A	p.Arg370Lys	missense_variant	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.1109G>A	p.Arg370Lys	missense_variant	3/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251426 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461838 Hom.: 0 Cov.: 40 AF XY: 0.0000509 AC XY: 37 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74268

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Apr 12, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2023	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 370 of the NLRP12 protein (p.Arg370Lys). This variant is present in population databases (rs764966959, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. ClinVar contains an entry for this variant (Variation ID: 580691). 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. 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	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.76	N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	D;N;D;N;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.20
MutPred		0.79		Gain of ubiquitination at R370 (P = 0.0185);Gain of ubiquitination at R370 (P = 0.0185);Gain of ubiquitination at R370 (P = 0.0185);Gain of ubiquitination at R370 (P = 0.0185);Gain of ubiquitination at R370 (P = 0.0185);
MVP		0.93
MPC		0.13
ClinPred		0.55	D
GERP RS		2.4
Varity_R		0.53
gMVP		0.61

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: rs764966959; hg19: chr19-54313804; COSMIC: COSV60756805; COSMIC: COSV60756805;