rs104895552

Positions:

• chr19-54936279-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001127255.2(NLRP7):​c.2282G>A​(p.Cys761Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.734

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.2282G>A	p.Cys761Tyr	missense_variant	6/11		NP_001120727.1
NLRP7	NM_001405531.1	c.2282G>A	p.Cys761Tyr	missense_variant	8/13		NP_001392460.1
NLRP7	NM_139176.4	c.2198G>A	p.Cys733Tyr	missense_variant	6/11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.2282G>A	p.Cys761Tyr	missense_variant	6/11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461282 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;.;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.068	N
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.6	M;.;M;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-9.7	D;.;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.68
MVP		0.67
MPC		1.1
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.74
gMVP		0.56

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: rs104895552; hg19: chr19-55447647;