rs104895503

chr19-54930571-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001405531.1(NLRP7):c.2738A>G(p.Asn913Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,612,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: NLRP7 NM_001405531.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.34

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-54930571-T-C is Pathogenic according to our data. Variant chr19-54930571-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1588.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in UniProt as null. Variant chr19-54930571-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP7	NM_001127255.2	c.2738A>G	p.Asn913Ser	missense_variant	9/11	ENST00000592784.6
NLRP7	NM_001405531.1	c.2738A>G	p.Asn913Ser	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP7	ENST00000592784.6	c.2738A>G	p.Asn913Ser	missense_variant	9/11	1	NM_001127255.2	P2

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251494 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135922

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000603 AC: 88 AN: 1460312 Hom.: 0 Cov.: 33 AF XY: 0.0000606 AC XY: 44 AN XY: 726614

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74444

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000136 Hom.: 1

Bravo AF: 0.000465

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Pathogenic:2 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 12, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.073	N
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.5	M;.;M;M;M
MutationTaster	Benign	3.1e-10	A;A;A;A;A;A;A
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D;.;.;.;.
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Uncertain	0.053	T;T;T;T;T
Polyphen		0.99	D;D;D;.;.
Vest4		0.71
MVP		0.57
MPC		0.74
ClinPred		0.15	T
GERP RS		1.4
Varity_R		0.30
gMVP		0.72

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: rs104895503; hg19: chr19-55441939;