rs4539722

Positions:

• chr19-53824186-G-A
• chr19-53824186-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144687.4(NLRP12):​c.-12C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,612,406 control chromosomes in the GnomAD database, including 233,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17175 hom., cov: 31)
  • Exomes 𝑓: 0.54 (216202 hom.)
• Consequence: NLRP12 NM_144687.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.624

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-53824186-G-A is Benign according to our data. Variant chr19-53824186-G-A is described in ClinVar as [Benign]. Clinvar id is 262527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53824186-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.-12C>T		5_prime_UTR_variant	1/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.-12C>T		5_prime_UTR_variant	1/10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.-12C>T		5_prime_UTR_variant	1/9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.-12C>T		5_prime_UTR_variant	1/7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68893 AN: 151838 Hom.: 17171 Cov.: 31

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.509

GnomAD3 exomes AF: 0.509 AC: 127254 AN: 249930 Hom.: 33533 AF XY: 0.515 AC XY: 69657 AN XY: 135222

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.643

Gnomad EAS exome AF: 0.540

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.540 AC: 788583 AN: 1460450 Hom.: 216202 Cov.: 46 AF XY: 0.539 AC XY: 391424 AN XY: 726542

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.470

Gnomad4 ASJ exome AF: 0.642

Gnomad4 EAS exome AF: 0.587

Gnomad4 SAS exome AF: 0.445

Gnomad4 FIN exome AF: 0.569

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.523

GnomAD4 genome AF: 0.454 AC: 68914 AN: 151956 Hom.: 17175 Cov.: 31 AF XY: 0.456 AC XY: 33878 AN XY: 74254

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.646

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.549

Gnomad4 OTH AF: 0.503

Alfa AF: 0.523 Hom.: 8868

Bravo AF: 0.440

Asia WGS AF: 0.436 AC: 1517 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 70. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Familial cold autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.9
DANN	Benign	0.85

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: rs4539722; hg19: chr19-54327440;