19-54930534-T-C

Variant names:

• chr19-54930534-T-C
• rs269950
• ENST00000588756.5:c.2775A>G

Variant summary

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

The NM_001127255.2(NLRP7):​c.2775A>G​(p.Ala925Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 1,607,408 control chromosomes in the GnomAD database, including 254,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23596 hom., cov: 31)
  • Exomes 𝑓: 0.56 (231219 hom.)
• Consequence: NLRP7 NM_001127255.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.83

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-54930534-T-C is Benign according to our data. Variant chr19-54930534-T-C is described in ClinVar as [Benign]. Clinvar id is 330156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54930534-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.2775A>G	p.Ala925Ala	synonymous_variant	Exon 9 of 11		NP_001120727.1
NLRP7	NM_001405531.1	c.2775A>G	p.Ala925Ala	synonymous_variant	Exon 11 of 13		NP_001392460.1
NLRP7	NM_139176.4	c.2691A>G	p.Ala897Ala	synonymous_variant	Exon 9 of 11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.2775A>G	p.Ala925Ala	synonymous_variant	Exon 9 of 11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84170 AN: 151810 Hom.: 23574 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.588 AC: 147847 AN: 251404 Hom.: 44116 AF XY: 0.589 AC XY: 80070 AN XY: 135880

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.716

Gnomad SAS exome AF: 0.630

Gnomad FIN exome AF: 0.553

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.561 AC: 817058 AN: 1455480 Hom.: 231219 Cov.: 33 AF XY: 0.565 AC XY: 409176 AN XY: 724438

Gnomad4 AFR exome AF: 0.511

Gnomad4 AMR exome AF: 0.639

Gnomad4 ASJ exome AF: 0.628

Gnomad4 EAS exome AF: 0.719

Gnomad4 SAS exome AF: 0.637

Gnomad4 FIN exome AF: 0.550

Gnomad4 NFE exome AF: 0.546

Gnomad4 OTH exome AF: 0.573

GnomAD4 genome AF: 0.554 AC: 84235 AN: 151928 Hom.: 23596 Cov.: 31 AF XY: 0.558 AC XY: 41416 AN XY: 74242

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.626

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.635

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.548

Alfa AF: 0.557 Hom.: 24432

Bravo AF: 0.554

Asia WGS AF: 0.619 AC: 2154 AN: 3478

EpiCase AF: 0.555

EpiControl AF: 0.552

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Benign:3

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 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 -

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
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.75
DANN	Benign	0.34

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: rs269950; hg19: chr19-55441902; COSMIC: COSV60172222;