19-53795919-G-T

Variant names:

• chr19-53795919-G-T
• rs538392013
• NM_144687.4:c.3038C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144687.4(NLRP12):​c.3038C>A​(p.Thr1013Lys) 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 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.525

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30847502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.3038C>A	p.Thr1013Lys	missense_variant	Exon 9 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.3038C>A	p.Thr1013Lys	missense_variant	Exon 9 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2934-1783C>A		intron_variant	Intron 8 of 8	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2592-1783C>A		intron_variant	Intron 6 of 6	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1013 of the NLRP12 protein (p.Thr1013Lys). This variant is not present in population databases (gnomAD no frequency). 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: 469094). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.6
DANN	Benign	0.49
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.026	T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.90	T;T;T
Sift4G	Benign	0.89	T;T;T
Polyphen		0.14	B;.;.
Vest4		0.46
MutPred		0.43		Gain of ubiquitination at T1013 (P = 0.0289);.;.;
MVP		0.62
MPC		0.061
ClinPred		0.084	T
GERP RS		0.80
Varity_R		0.034
gMVP		0.38

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: rs538392013; hg19: chr19-54299173;