19-53824314-A-T

Variant names:

• chr19-53824314-A-T
• rs4419163
• NM_144687.4:c.-140T>A

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.-140T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 813,216 control chromosomes in the GnomAD database, including 249,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47053 hom., cov: 30)
  • Exomes 𝑓: 0.78 (202906 hom.)
• Consequence: NLRP12 NM_144687.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.38
• Publications: 11 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=-0.92).
• BP6: Variant 19-53824314-A-T is Benign according to our data. Variant chr19-53824314-A-T is described in ClinVar as Benign. ClinVar VariationId is 330052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144687.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.-140T>A		5_prime_UTR	Exon 1 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.-140T>A		5_prime_UTR	Exon 1 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.-140T>A		5_prime_UTR	Exon 1 of 9	NP_001264058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.-140T>A		5_prime_UTR	Exon 1 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.-140T>A		5_prime_UTR	Exon 1 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.-140T>A		5_prime_UTR	Exon 1 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119457 AN: 151840 Hom.: 47000 Cov.: 30

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.799

GnomAD4 exome AF: 0.783 AC: 517809 AN: 661258 Hom.: 202906 Cov.: 9 AF XY: 0.784 AC XY: 271382 AN XY: 346186

African (AFR) AF: 0.788 AC: 14367 AN: 18240

American (AMR) AF: 0.743 AC: 23186 AN: 31204

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 15245 AN: 18660

East Asian (EAS) AF: 0.753 AC: 24321 AN: 32304

South Asian (SAS) AF: 0.792 AC: 50026 AN: 63162

European-Finnish (FIN) AF: 0.774 AC: 26392 AN: 34096

Middle Eastern (MID) AF: 0.752 AC: 2053 AN: 2730

European-Non Finnish (NFE) AF: 0.786 AC: 336057 AN: 427468

Other (OTH) AF: 0.783 AC: 26162 AN: 33394

GnomAD4 genome AF: 0.787 AC: 119564 AN: 151958 Hom.: 47053 Cov.: 30 AF XY: 0.786 AC XY: 58348 AN XY: 74264

African (AFR) AF: 0.795 AC: 32950 AN: 41434

American (AMR) AF: 0.756 AC: 11517 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2828 AN: 3470

East Asian (EAS) AF: 0.753 AC: 3874 AN: 5146

South Asian (SAS) AF: 0.788 AC: 3795 AN: 4814

European-Finnish (FIN) AF: 0.760 AC: 8038 AN: 10572

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 53951 AN: 67974

Other (OTH) AF: 0.793 AC: 1668 AN: 2104

Alfa AF: 0.788 Hom.: 4858

Bravo AF: 0.786

Asia WGS AF: 0.735 AC: 2559 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

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 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.48
DANN	Benign	0.36
PhyloP100		-2.4
PromoterAI		0.032	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: rs4419163; hg19: chr19-54327568; COSMIC: COSV60757137;