Genetic Variant NLRP7:p.Arg701Gly (chr19-54938072-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001127255.2(NLRP7):c.2101C>G(p.Arg701Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R701C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NLRP7
NM_001127255.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0700

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001127255.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10932088).

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.2101C>G	p.Arg701Gly	missense	Exon 5 of 11	NP_001120727.1
NLRP7	NM_001405531.1		c.2101C>G	p.Arg701Gly	missense	Exon 7 of 13	NP_001392460.1
NLRP7	NM_139176.4		c.2017C>G	p.Arg673Gly	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.2101C>G	p.Arg701Gly	missense	Exon 5 of 11	ENSP00000468706.1
NLRP7	ENST00000588756.5	TSL:1	c.2101C>G	p.Arg701Gly	missense	Exon 7 of 13	ENSP00000467123.1
NLRP7	ENST00000340844.6	TSL:1	c.2101C>G	p.Arg701Gly	missense	Exon 5 of 10	ENSP00000339491.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251494

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.43

CADD

Benign

2.6

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.030

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.11

M_CAP

Benign

0.0051

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.99

MutationAssessor

Benign

2.0

PhyloP100

-0.070

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.99

REVEL

Benign

0.089

Sift

Benign

0.70

Sift4G

Benign

0.38

Polyphen

0.80

Vest4

0.28

MVP

0.26

MPC

0.41

ClinPred

0.11

GERP RS

-1.5

Varity_R

0.072

gMVP

0.30

Mutation Taster

=67/33

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over