19-54939681-C-G

Position:

• chr19-54939681-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001127255.2(NLRP7):​c.1138G>C​(p.Gly380Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,190 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (11 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.741

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010307968).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000304 (444/1460992) while in subpopulation SAS AF= 0.00458 (395/86216). AF 95% confidence interval is 0.00421. There are 11 homozygotes in gnomad4_exome. There are 319 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.1138G>C	p.Gly380Arg	missense_variant	4/11		NP_001120727.1
NLRP7	NM_001405531.1	c.1138G>C	p.Gly380Arg	missense_variant	6/13		NP_001392460.1
NLRP7	NM_139176.4	c.1138G>C	p.Gly380Arg	missense_variant	4/11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.1138G>C	p.Gly380Arg	missense_variant	4/11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000666 AC: 166 AN: 249364 Hom.: 6 AF XY: 0.000917 AC XY: 124 AN XY: 135264

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00519

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1460992 Hom.: 11 Cov.: 36 AF XY: 0.000439 AC XY: 319 AN XY: 726820

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00458

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74402

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000758 AC: 92

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Uncertain:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.040	N
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-6.3	D;D;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.030	D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.18
MVP		0.47
MPC		0.96
ClinPred		0.18	T
GERP RS		1.9
Varity_R		0.17
gMVP		0.57

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: rs104895557; hg19: chr19-55451049;