19-54939682-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001405531.1(NLRP7):c.1137G>A(p.Lys379=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,612,666 control chromosomes in the GnomAD database, including 36,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2952 hom., cov: 31)
  • Exomes 𝑓: 0.21 (33807 hom.)
• Consequence: NLRP7 NM_001405531.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.88

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-54939682-C-T is Benign according to our data. Variant chr19-54939682-C-T is described in ClinVar as [Benign]. Clinvar id is 330172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54939682-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP7	NM_001127255.2	c.1137G>A	p.Lys379=	synonymous_variant	4/11	ENST00000592784.6
NLRP7	NM_001405531.1	c.1137G>A	p.Lys379=	synonymous_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP7	ENST00000592784.6	c.1137G>A	p.Lys379=	synonymous_variant	4/11	1	NM_001127255.2	P2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28674 AN: 151800 Hom.: 2948 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.212 AC: 52890 AN: 249060 Hom.: 5921 AF XY: 0.211 AC XY: 28555 AN XY: 135116

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.213 AC: 311722 AN: 1460750 Hom.: 33807 Cov.: 74 AF XY: 0.213 AC XY: 154719 AN XY: 726708

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.189 AC: 28688 AN: 151916 Hom.: 2952 Cov.: 31 AF XY: 0.191 AC XY: 14213 AN XY: 74254

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.201

Alfa AF: 0.133 Hom.: 322

Bravo AF: 0.189

EpiCase AF: 0.208

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.33
Dann	Benign	0.47

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: rs10418277; hg19: chr19-55451050; COSMIC: COSV60174398; COSMIC: COSV60174398;