rs104895506

chr19-54938096-G-Achr19-54938096-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_001405531.1(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 NM_001405531.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -0.172

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]

NCR1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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	UniProt
NLRP7	NM_001127255.2	c.2077C>T	p.Arg693Trp	missense_variant	5/11	ENST00000592784.6
NLRP7	NM_001405531.1	c.2077C>T	p.Arg693Trp	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP7	ENST00000592784.6	c.2077C>T	p.Arg693Trp	missense_variant	5/11	1	NM_001127255.2	P2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152096 Hom.: 0 Cov.: 32

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: 69 AN: 251496 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135922

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.: 1 Cov.: 33 AF XY: 0.000190 AC XY: 138 AN XY: 727228

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: 35 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74292

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.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Pathogenic:2 Other: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	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.39	N
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M;.;M;M;M
MutationTaster	Benign	0.00025	A;A;A;A;A;A;A
PrimateAI	Benign	0.44	T
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	D
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

Other links and lift over

dbSNP: rs104895506; hg19: chr19-55449464; COSMIC: COSV60172954; COSMIC: COSV60172954;