rs104895549

Positions:

• chr19-54938222-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001127255.2(NLRP7):​c.1951C>T​(p.Pro651Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P651L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.461

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-54938222-G-A is Pathogenic according to our data. Variant chr19-54938222-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1593.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null. Variant chr19-54938222-G-A is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41765282). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.1951C>T	p.Pro651Ser	missense_variant	5/11		NP_001120727.1
NLRP7	NM_001405531.1	c.1951C>T	p.Pro651Ser	missense_variant	7/13		NP_001392460.1
NLRP7	NM_206828.4	c.1951C>T	p.Pro651Ser	missense_variant	5/10		NP_996611.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.1951C>T	p.Pro651Ser	missense_variant	5/11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2009	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	2.8
DANN	Benign	0.79
DEOGEN2	Benign	0.035	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.064	N
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.080	N;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.20	T;.;.;.
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.20	B;B;.;.
Vest4		0.31
MVP		0.21
MPC		0.26
ClinPred		0.081	T
GERP RS		-0.49
Varity_R		0.11
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs104895549; hg19: chr19-55449590; COSMIC: COSV60173292; COSMIC: COSV60173292;