NM_144687.4:c.2073-5A>G

Variant names:

• chr19-53807670-T-C
• rs1555795098
• NM_144687.4:c.2073-5A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144687.4(NLRP12):​c.2073-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP12 NM_144687.4 splice_region, intron
• Scores: Splicing: ADA: 0.005832
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.415

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2073-5A>G		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.2073-5A>G		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2073-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 8	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2073-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 6	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:1

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the NLRP12 gene. It does not directly change the encoded amino acid sequence of the NLRP12 protein. 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: 469092). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	18
DANN	Benign	0.55
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.017	N
GERP RS		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0058
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555795098; hg19: chr19-54310924;