chr19-54938095-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP5_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. R693W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

NLRP7
NM_001127255.2 missense

Scores

1
8
9

Clinical Significance

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

Conservation

PhyloP100: -0.00300
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 chr19-54938096-G-A is described in Lovd as [Likely_pathogenic].
PP5
Variant 19-54938095-C-G is Pathogenic according to our data. 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. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in UniProt as null. Variant chr19-54938095-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NLRP7NM_001127255.2 linkuse as main transcriptc.2078G>C p.Arg693Pro missense_variant 5/11 NP_001120727.1 Q8WX94-3
NLRP7NM_001405531.1 linkuse as main transcriptc.2078G>C p.Arg693Pro missense_variant 7/13 NP_001392460.1
NLRP7NM_139176.4 linkuse as main transcriptc.1994G>C p.Arg665Pro missense_variant 5/11 NP_631915.2 Q8WX94-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NLRP7ENST00000592784.6 linkuse as main transcriptc.2078G>C p.Arg693Pro missense_variant 5/111 ENSP00000468706.1 Q8WX94-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152030
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251494
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135922
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 SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000568
AC:
83
AN:
1461870
Hom.:
0
Cov.:
33
AF XY:
0.0000578
AC XY:
42
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152030
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74222
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:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
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
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyJul 18, 2023The 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). -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2009- -
not provided, no classification providedliterature onlyUnité médicale des maladies autoinflammatoires, CHRU Montpellier-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Benign
0.0064
T
BayesDel_noAF
Uncertain
0.070
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.19
T;.;T;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.31
N
M_CAP
Benign
0.0073
T
MetaRNN
Uncertain
0.67
D;D;D;D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.2
M;.;M;M;M
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-3.7
D;.;.;.;.
REVEL
Uncertain
0.34
Sift
Uncertain
0.011
D;.;.;.;.
Sift4G
Uncertain
0.0070
D;D;D;D;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.73
MVP
0.59
MPC
1.0
ClinPred
0.54
D
GERP RS
1.1
Varity_R
0.73
gMVP
0.71

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.

Other links and lift over

dbSNP: rs104895502; hg19: chr19-55449463; API