rs4539722

Variant names:

• chr19-53824186-G-A
• rs4539722
• NM_144687.4:c.-12C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• familial cold autoinflammatory syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.-12C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.-12C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.-12C>T		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.-12C>T		5_prime_UTR_variant	Exon 1 of 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

GnomAD2 exomes AF: 0.509 AC: 127254 AN: 249930 AF XY: 0.515

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 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

African (AFR) AF: 0.216 AC: 7231 AN: 33462

American (AMR) AF: 0.470 AC: 20985 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 16767 AN: 26128

East Asian (EAS) AF: 0.587 AC: 23318 AN: 39694

South Asian (SAS) AF: 0.445 AC: 38378 AN: 86218

European-Finnish (FIN) AF: 0.569 AC: 30037 AN: 52760

Middle Eastern (MID) AF: 0.522 AC: 3003 AN: 5756

European-Non Finnish (NFE) AF: 0.555 AC: 617284 AN: 1111374

Other (OTH) AF: 0.523 AC: 31580 AN: 60372

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

African (AFR) AF: 0.231 AC: 9570 AN: 41454

American (AMR) AF: 0.477 AC: 7273 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2242 AN: 3472

East Asian (EAS) AF: 0.554 AC: 2849 AN: 5146

South Asian (SAS) AF: 0.430 AC: 2071 AN: 4814

European-Finnish (FIN) AF: 0.563 AC: 5953 AN: 10566

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37336 AN: 67950

Other (OTH) AF: 0.503 AC: 1061 AN: 2110

Alfa AF: 0.530 Hom.: 13436

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cold autoinflammatory syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.9
DANN	Benign	0.85
PhyloP100		0.62
PromoterAI		0.012	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4539722; hg19: chr19-54327440;