ENST00000588756.5:c.955G>A

Variant names:

• chr19-54939864-C-T
• rs775882
• ENST00000588756.5:c.955G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000588756.5(NLRP7):​c.955G>A​(p.Val319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,596 control chromosomes in the GnomAD database, including 46,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7509 hom., cov: 31)
  • Exomes 𝑓: 0.23 (38636 hom.)
• Consequence: NLRP7 ENST00000588756.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.873672E-4).
• BP6: Variant 19-54939864-C-T is Benign according to our data. Variant chr19-54939864-C-T is described in ClinVar as [Benign]. Clinvar id is 330176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54939864-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.955G>A	p.Val319Ile	missense_variant	Exon 4 of 11		NP_001120727.1
NLRP7	NM_001405531.1	c.955G>A	p.Val319Ile	missense_variant	Exon 6 of 13		NP_001392460.1
NLRP7	NM_139176.4	c.955G>A	p.Val319Ile	missense_variant	Exon 4 of 11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.955G>A	p.Val319Ile	missense_variant	Exon 4 of 11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44178 AN: 151846 Hom.: 7478 Cov.: 31

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.287

GnomAD3 exomes AF: 0.241 AC: 60578 AN: 251130 Hom.: 8038 AF XY: 0.233 AC XY: 31693 AN XY: 135788

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.225 AC: 329397 AN: 1461632 Hom.: 38636 Cov.: 75 AF XY: 0.224 AC XY: 162574 AN XY: 727120

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.291 AC: 44264 AN: 151964 Hom.: 7509 Cov.: 31 AF XY: 0.290 AC XY: 21563 AN XY: 74280

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.285

Alfa AF: 0.201 Hom.: 3065

Bravo AF: 0.306

TwinsUK AF: 0.221 AC: 819

ALSPAC AF: 0.211 AC: 815

ESP6500AA AF: 0.462 AC: 2034

ESP6500EA AF: 0.210 AC: 1808

ExAC AF: 0.241 AC: 29263

Asia WGS AF: 0.249 AC: 867 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.214

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Hydatidiform mole, recurrent, 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0090
DANN	Benign	0.14
DEOGEN2	Benign	0.033	T;.;T;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0055	N
MetaRNN	Benign	0.00019	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.015	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.050	N;N;.;.;.
REVEL	Benign	0.095
Sift	Benign	0.94	T;T;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0040	B;B;B;.;.
Vest4		0.015
MPC		0.21
ClinPred		0.00072	T
GERP RS		-3.1
Varity_R		0.025
gMVP		0.12

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: rs775882; hg19: chr19-55451232; COSMIC: COSV60170800; COSMIC: COSV60170800;