chr19-54936313-G-C

Position:

chr19-54936313-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

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 (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

NLRP7
NM_001405531.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 0.475

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 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	Protein	UniProt
NLRP7	NM_001127255.2 linkuse as main transcript	c.2248C>G	p.Leu750Val	missense_variant	6/11	ENST00000592784.6	NP_001120727.1
NLRP7	NM_001405531.1 linkuse as main transcript	c.2248C>G	p.Leu750Val	missense_variant	8/13		NP_001392460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6 linkuse as main transcript	c.2248C>G	p.Leu750Val	missense_variant	6/11	1	NM_001127255.2	ENSP00000468706	P2	Q8WX94-3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000353

AC XY:

AN XY:

135886

show subpopulations

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.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727180

show subpopulations

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:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.000283

ExAC

AF:

0.000478

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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) -

Hydatidiform mole, recurrent, 1

Pathogenic:1Other: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

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

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0083

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.0

M;.;M;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.29

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

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

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