chr19-53810749-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H304Q) has been classified as Uncertain significance.

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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: {Uncertain_significance=1, Likely_benign=3, Benign=5}. 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 the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4 link	c.910C>T	p.His304Tyr	missense_variant	Exon 3 of 10	ENST00000324134.11	NP_653288.1	P59046-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLRP12	ENST00000324134.11 link	c.910C>T	p.His304Tyr	missense_variant	Exon 3 of 10	1	NM_144687.4	ENSP00000319377.6	P59046-1
NLRP12	ENST00000345770.9 link	c.910C>T	p.His304Tyr	missense_variant	Exon 3 of 9	1		ENSP00000341428.5	A0A0C4DH17
NLRP12	ENST00000391772.1 link	c.910C>T	p.His304Tyr	missense_variant	Exon 3 of 7	1		ENSP00000375652.1	A0A0C4DFY3

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

GnomAD2 exomes

AF:

0.00432

AC:

1086

AN:

251246

AF XY:

0.00430

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 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

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00288

AC:

129

AN:

44724

Gnomad4 ASJ exome

AF:

0.00696

AC:

182

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00110

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0224

AC:

1195

AN:

53378

Gnomad4 NFE exome

AF:

0.00340

AC:

3778

AN:

1112012

Gnomad4 Remaining exome

AF:

0.00356

AC:

215

AN:

60396

Heterozygous variant carriers

379

758

1138

1517

1896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.000601743

AN:

0.000601743

Gnomad4 AMR

AF:

0.00157

AC:

0.00157336

AN:

0.00157336

Gnomad4 ASJ

AF:

0.00922

AC:

0.00921659

AN:

0.00921659

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000829

AC:

0.000828844

AN:

0.000828844

Gnomad4 FIN

AF:

0.0214

AC:

0.0213828

AN:

0.0213828

Gnomad4 NFE

AF:

0.00366

AC:

0.00366112

AN:

0.00366112

Gnomad4 OTH

AF:

0.00616

AC:

0.00616114

AN:

0.00616114

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00308

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

Oct 13, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NLRP12: BP4, BS1, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

May 03, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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;.;.

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

Mutation Taster

=78/22

polymorphism

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