chr19-53793855-G-A

Position:

• chr19-53793855-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144687.4(NLRP12):​c.*194C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 672,432 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (18 hom.)
• Consequence: NLRP12 NM_144687.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.176

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-53793855-G-A is Benign according to our data. Variant chr19-53793855-G-A is described in ClinVar as [Benign]. Clinvar id is 894483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000625 (95/152040) while in subpopulation SAS AF= 0.016 (77/4804). AF 95% confidence interval is 0.0131. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.*194C>T		3_prime_UTR_variant	10/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.*194C>T		3_prime_UTR_variant	10/10	1	NM_144687.4	ENSP00000319377	P4

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 151922 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00175 AC: 911 AN: 520392 Hom.: 18 Cov.: 3 AF XY: 0.00246 AC XY: 689 AN XY: 279738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000617

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.0000316

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000897

GnomAD4 genome AF: 0.000625 AC: 95 AN: 152040 Hom.: 0 Cov.: 31 AF XY: 0.000848 AC XY: 63 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.000212

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.43

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: rs557195352; hg19: chr19-54297109;