rs104895506

Positions:

Variant summary

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

The ENST00000592784.6(NLRP7):c.2077C>T(p.Arg693Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R693P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

NLRP7
ENST00000592784.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.172

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-G is described in ClinVar as [Pathogenic]. Clinvar id is 1587.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 19-54938096-G-A is Pathogenic according to our data. Variant chr19-54938096-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1586.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in UniProt as null. Variant chr19-54938096-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP7	NM_001127255.2 linkuse as main transcript	c.2077C>T	p.Arg693Trp	missense_variant	5/11	ENST00000592784.6	NP_001120727.1
NLRP7	NM_001405531.1 linkuse as main transcript	c.2077C>T	p.Arg693Trp	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.2077C>T	p.Arg693Trp	missense_variant	5/11	1	NM_001127255.2	ENSP00000468706	P2	Q8WX94-3

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152096

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:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000274

AC:

AN:

251496

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000198

AC:

290

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00225

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000230

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74292

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:

0.00254

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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	Illumina Laboratory Services, Illumina	Apr 28, 2017	The NLRP7 c.2077C>T (p.Arg693Trp) variant is one of the most common variants found in recurrent hydatidiform mole (RHM). The variant has been reported in at least six studies in which it is found in nine affected individuals, including three in a homozygous state, three in a compound heterozygous state, and three of unknown zygosity (Murdoch et al. 2006; Puechberty et al. 2009; Wang et al. 2009; Messaed et al. 2011; Dixon et al. 2012; Sebire et al. 2013). The p.Arg693Trp variant was absent from 1524 control chromosomes and is reported at a frequency of 0.00302 in the European (Finnish) population of the Exome Aggregation Consortium. Co-immunoprecipitation studies with the p.Arg693Trp variant protein showed reduced dimer formation compared to wild type (Singer et al. 2014). The p.Arg693Trp variant protein was also found to be more potent at activating inflammasome complexes compared to wild type protein (Khare et al. 2012). Based on the collective evidence, the p.Arg693Trp variant is classified as pathogenic for recurrent hydatidiform mole. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 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

Benign

0.28

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.39

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.5

M;.;M;M;M

MutationTaster

Benign

0.00025

A;A;A;A;A;A;A

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.0

D;.;.;.;.

REVEL

Benign

0.28

Sift

Uncertain

0.0020

D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.71

MVP

0.64

MPC

0.89

ClinPred

0.76

GERP RS

-0.15

Varity_R

0.22

gMVP

0.46

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