19-54938095-C-G

Position:

chr19-54938095-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate

The ENST00000592784.6(NLRP7):c.2078G>C(p.Arg693Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R693Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

NLRP7
ENST00000592784.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: -0.00300

Variant links:

Genes affected

NLRP7 (HGNC:22947): (NLR family pyrin domain containing 7) This gene encodes a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family. It has an N-terminal pyrin domain, followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NLRP proteins are implicated in the activation of proinflammatory caspases through multiprotein complexes called inflammasomes. This gene may act as a feedback regulator of caspase-1-dependent interleukin 1-beta secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

NLRP7 links:

NCR1 (HGNC:):

NCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a repeat LRR 2 (size 23) in uniprot entity NALP7_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000592784.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-54938095-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1591.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 19-54938095-C-G is Pathogenic according to our data. Variant chr19-54938095-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1587.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP7	NM_001127255.2 linkuse as main transcript	c.2078G>C	p.Arg693Pro	missense_variant	5/11	ENST00000592784.6	NP_001120727.1
NLRP7	NM_001405531.1 linkuse as main transcript	c.2078G>C	p.Arg693Pro	missense_variant	7/13		NP_001392460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6 linkuse as main transcript	c.2078G>C	p.Arg693Pro	missense_variant	5/11	1	NM_001127255.2	ENSP00000468706	P2	Q8WX94-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251494

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hydatidiform mole, recurrent, 1

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 18, 2023	The NLRP7 c.2078G>C variant is classified as PATHOGENIC (PM5, PM3_Strong, PP1_Strong, PS3_Supporting, PP4). The NLRP7 c.2078G>C variant is a single nucleotide change in exon 5/11 of the NLRP7 gene, which is predicted to change the amino acid arginine at position 693 in the protein to proline. This variant is a missense change at an amino acid residue where two different pathogenic missense changes have been seen before: p.(Arg693Gln) and p.(Arg693Trp) (ClinVar Variation IDs: 1591, 1586) (PM5). This variant has been detected homozygous or compound heterozygous with a pathogenic variant in multiple unrelated families (PMID: 16462743, 19246479) (PM3_Strong). This variant co-segregates with disease and has been detected homozogyous or compound heterozygous with a pathogenic variant in six unrelated, non-consanguineous Indian/Pakistani families. Haplotype analysis showed a common haplotype associated with the pathogenic variant, suggesting a potential founder mutation (PMID: 19650864) (PP1_Strong). Genome-wide methylation studies on molar tissue from two sisters homozygous for the variant demonstrated aberrant methylation at maternal differentially methylated regions compared to non-molar normal placental tissue (PMID: 26544189) (PS3_Supporting). The clinical history is highly specific for the NLRP7 gene (PP4). The variant has been reported in dbSNP (rs104895502) and is present in population databases (gnomAD v3.1.2 allele frequency = 0.002%, 3 het/152030 alleles). It is reported as disease causing in the HGMD database (CM061147) and is reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 1587). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

0.0064

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;.;T;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.31

M_CAP

Benign

0.0073

MetaRNN

Uncertain

0.67

D;D;D;D;D

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.2

M;.;M;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.7

D;.;.;.;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.011

D;.;.;.;.

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.73

MVP

0.59

MPC

1.0

ClinPred

0.54

GERP RS

1.1

Varity_R

0.73

gMVP

0.71

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

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