rs35064500

Variant names:

• chr19-53795911-G-A
• rs35064500
• NM_144687.4:c.3046C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-53795911-G-A
• chr19-53795911-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_144687.4(NLRP12):​c.3046C>T​(p.Arg1016*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,614,096 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (8 hom.)
• Consequence: NLRP12 NM_144687.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4 O:1
• Conservation: PhyloP100: -0.991

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 -7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0439 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 19-53795911-G-A is Benign according to our data. Variant chr19-53795911-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330001.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00426 (649/152226) while in subpopulation AFR AF= 0.0149 (618/41534). AF 95% confidence interval is 0.0139. There are 3 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 649 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.3046C>T	p.Arg1016*	stop_gained	Exon 9 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.3046C>T	p.Arg1016*	stop_gained	Exon 9 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2934-1775C>T		intron_variant	Intron 8 of 8	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2592-1775C>T		intron_variant	Intron 6 of 6	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 650 AN: 152108 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 251376 Hom.: 2 AF XY: 0.00102 AC XY: 138 AN XY: 135886

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000632 AC: 924 AN: 1461870 Hom.: 8 Cov.: 32 AF XY: 0.000583 AC XY: 424 AN XY: 727236

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000254

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152226 Hom.: 3 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74424

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000880 Hom.: 2

Bravo AF: 0.00498

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:2 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 06, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NLRP12 c.3046C>T; p.Arg1016Ter variant (rs35064500) is present in the African population with an allele frequency of 1.6% (401/24,956 alleles including 3 homozygotes) in the Genome Aggregation Database v2.1.1. To our knowledge, the variant has not been reported in any individuals with familial cold autoinflammatory syndrome, but has been reported in individuals with unrelated or non-specific conditions (Modi 2017, Ung 2017, Glicksberg 2019, El Naofal 2023) and is listed in the ClinVar Database (Variation ID: 330001). This variant results in a premature termination codon in the penultimate exon of the NLRP12 gene and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Although the allele frequency of this variant may be incompatible with autosomal dominant familial autoinflammatory syndrome, given the lack of clinical and functional data, the significance of the p.Arg1016Ter variant is uncertain at this time. References: El Naofal M et al. The genomic landscape of rare disorders in the Middle East. Genome Med. 2023 Jan 27;15(1):5. PMID: 36703223 Glicksberg BS et al. Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. BMC Med Genomics. 2019 Jul 25;12(Suppl 6):108. PMID: 31345219 Modi BP et al. Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM). Mol Genet Genomic Med. 2017 Nov;5(6):720-729. Ung C et al. Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Res. 2017 Oct;139:168-176. -

not provided Uncertain:1

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NLRP12-related disorder Benign:1

Jan 06, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autoinflammatory syndrome Benign:1

Apr 13, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multisystem inflammatory syndrome in children Other:1

Nov 14, 2021

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Benign	0.95
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.021	N
Vest4		0.89
GERP RS		-1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35064500; hg19: chr19-54299165; COSMIC: COSV60750588;