chr19-53810749-G-A

Position:

chr19-53810749-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144687.4(NLRP12):c.910C>T(p.His304Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,614,044 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0038 ( 21 hom. )

Consequence

NLRP12
NM_144687.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.18

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007107258).

BP6

Variant 19-53810749-G-A is Benign according to our data. Variant chr19-53810749-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262532.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=5, Uncertain_significance=1}. Variant chr19-53810749-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00377 (574/152192) while in subpopulation NFE AF= 0.00366 (249/68012). AF 95% confidence interval is 0.00329. There are 4 homozygotes in gnomad4. There are 337 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4 linkuse as main transcript	c.910C>T	p.His304Tyr	missense_variant	3/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11 linkuse as main transcript	c.910C>T	p.His304Tyr	missense_variant	3/10	1	NM_144687.4	ENSP00000319377	P4	P59046-1

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

574

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00366

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00432

AC:

1086

AN:

251246

Hom.:

AF XY:

0.00430

AC XY:

584

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.00676

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.00359

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00384

AC:

5619

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

2702

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.00696

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00110

Gnomad4 FIN exome

AF:

0.0224

Gnomad4 NFE exome

AF:

0.00340

Gnomad4 OTH exome

AF:

0.00356

GnomAD4 genome

AF:

0.00377

AC:

574

AN:

152192

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

337

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0214

Gnomad4 NFE

AF:

0.00366

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00318

Hom.:

Bravo

AF:

0.00241

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00422

AC:

513

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00349

EpiControl

AF:

0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 13, 2022	This variant has been reported in the literature in several individuals with features of immunodeficiency or autoimmunity, including periodic fevers, in the heterozygous and compound heterozygous state (Borte 2014 PMID: 25064829, Rusmini 2016 PMID: 26386126, Cetinkaya 2018 PMID: 29307770, Kostik 2018 PMID: 29500522, Ledesma 2019 PMID: 31836009, Suspitsin 2020 PMID: 32441320). This variant is present in the Genome Aggregation Database (Highest reported MAF: 2.1% [515/25100], including 3 homozygotes; https://gnomad.broadinstitute.org/variant/19-54314003-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID: 262532). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause Mendelian disease but requires further evidence. Therefore, this variant is classified as likely benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NLRP12: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;.;.;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.099

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.64

T;T;T;T;T

MetaRNN

Benign

0.0071

T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.5

M;M;M;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.2

N;N;N;N;N

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.42

MVP

0.90

MPC

0.36

ClinPred

0.018

GERP RS

3.4

Varity_R

0.52

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over