rs104895512

chr19-54936313-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001405531.1(NLRP7):c.2248C>G(p.Leu750Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L750L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: NLRP7 NM_001405531.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.475

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-54936313-G-C is Pathogenic according to our data. Variant chr19-54936313-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 97750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54936313-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.008270323).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP7	NM_001127255.2	c.2248C>G	p.Leu750Val	missense_variant	6/11	ENST00000592784.6
NLRP7	NM_001405531.1	c.2248C>G	p.Leu750Val	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP7	ENST00000592784.6	c.2248C>G	p.Leu750Val	missense_variant	6/11	1	NM_001127255.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000529 AC: 133 AN: 251412 Hom.: 0 AF XY: 0.000353 AC XY: 48 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1461750 Hom.: 0 Cov.: 34 AF XY: 0.0000811 AC XY: 59 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000297 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000478 AC: 58

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23354651, 26956250, 24105752, 18039680, 19066229, 21659348, 33583041, 34189227, 33751332) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 13, 2019	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in multiple individuals affected with autosomal recessive familial recurrent hydatidiform mole 1 (PMID: 18039680, 26956250, 19066229, 23354651) and it is found at high frequency in control individuals of Mexican descent (PMID: 23354651). ClinVar contains an entry for this variant (Variation ID: 97750). This variant is present in population databases (rs104895512, ExAC 0.5%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces leucine with valine at codon 750 of the NLRP7 protein (p.Leu750Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. -

Hydatidiform mole, recurrent, 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2018	The NLRP7 c.2248C>G (p.Leu750Val) variant has been reported three studies and is found in a total of 21 probands with recurrent hydatidiform mole including 15 in a homozygous state, six in a compound heterozygous state, and at least five in a heterozygous state (Kou et al. 2008; Deveault et al. 2009; Estrada et al. 2013). One of the homozygous probands had unaffected parents and sister that were heterozygous for the p.Leu750Val variant (Deveault et al. 2009). The p.Leu750Val variant was reported in five of 460 control chromosomes and is reported at a frequency of 0.005023 in the Latino population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Leu750Val is classified as pathogenic for hydatidiform mole. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	8.0
Dann	Benign	0.96
DEOGEN2	Benign	0.027	T;.;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.052	N
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.0083	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M;.;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.13	N;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.10	T;.;.;.;.
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.90	P;P;P;.;.
Vest4		0.48
MVP		0.40
MPC		0.46
ClinPred		0.048	T
GERP RS		1.2
Varity_R		0.044
gMVP		0.10

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: rs104895512; hg19: chr19-55447681;