19-54938095-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5PP5_Moderate

The NM_001127255.2(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
NM_001127255.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00300

Publications

15 publications found

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:6731): (natural cytotoxicity triggering receptor 1) Predicted to be involved in cellular defense response; regulation of natural killer cell mediated cytotoxicity; and signal transduction. Predicted to act upstream of or within defense response to virus and detection of virus. Predicted to be located in cell surface. Predicted to be part of SWI/SNF complex. Predicted to be active in plasma membrane. Biomarker of acquired immunodeficiency syndrome; anogenital venereal wart; hepatitis C; and lymphoproliferative syndrome. [provided by Alliance of Genome Resources, Apr 2022]

NCR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-54938095-C-T is described in ClinVar as Pathogenic. ClinVar VariationId 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 VariationId is 1587.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127255.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP7	NM_001127255.2	MANE Select	c.2078G>C	p.Arg693Pro	missense	Exon 5 of 11	NP_001120727.1
NLRP7	NM_001405531.1		c.2078G>C	p.Arg693Pro	missense	Exon 7 of 13	NP_001392460.1
NLRP7	NM_139176.4		c.1994G>C	p.Arg665Pro	missense	Exon 5 of 11	NP_631915.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.2078G>C	p.Arg693Pro	missense	Exon 5 of 11	ENSP00000468706.1
NLRP7	ENST00000588756.5	TSL:1	c.2078G>C	p.Arg693Pro	missense	Exon 7 of 13	ENSP00000467123.1
NLRP7	ENST00000340844.6	TSL:1	c.2078G>C	p.Arg693Pro	missense	Exon 5 of 10	ENSP00000339491.2

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

GnomAD2 exomes

AF:

0.0000477

AC:

AN:

251494

AF XY:

0.0000441

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1111994

Other (OTH)

AF:

0.000116

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Jul 18, 2023

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

0.0064

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.31

M_CAP

Benign

0.0073

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.2

PhyloP100

-0.0030

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.34

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.73

MVP

0.59

MPC

1.0

ClinPred

0.54

GERP RS

1.1

Varity_R

0.73

gMVP

0.71

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over