rs775883

Variant names:

• chr19-54940429-C-T
• rs775883
• ENST00000588756.5:c.390G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000588756.5(NLRP7):​c.390G>A​(p.Gln130Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,613,056 control chromosomes in the GnomAD database, including 99,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12081 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87601 hom.)
• Consequence: NLRP7 ENST00000588756.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.74
• Publications: 23 publications found

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]

NLRP7 Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• complete hydatidiform mole

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 19-54940429-C-T is Benign according to our data. Variant chr19-54940429-C-T is described in ClinVar as Benign. ClinVar VariationId is 330183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.390G>A	p.Gln130Gln	synonymous_variant	Exon 4 of 11		NP_001120727.1
NLRP7	NM_001405531.1	c.390G>A	p.Gln130Gln	synonymous_variant	Exon 6 of 13		NP_001392460.1
NLRP7	NM_139176.4	c.390G>A	p.Gln130Gln	synonymous_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.390G>A	p.Gln130Gln	synonymous_variant	Exon 4 of 11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58899 AN: 151894 Hom.: 12050 Cov.: 32

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.383

GnomAD2 exomes AF: 0.341 AC: 85406 AN: 250632 AF XY: 0.333

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.342 AC: 500020 AN: 1461044 Hom.: 87601 Cov.: 37 AF XY: 0.339 AC XY: 246746 AN XY: 726892

African (AFR) AF: 0.511 AC: 17115 AN: 33464

American (AMR) AF: 0.380 AC: 17000 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 9345 AN: 26130

East Asian (EAS) AF: 0.189 AC: 7489 AN: 39696

South Asian (SAS) AF: 0.267 AC: 23068 AN: 86246

European-Finnish (FIN) AF: 0.395 AC: 21067 AN: 53382

Middle Eastern (MID) AF: 0.364 AC: 2100 AN: 5768

European-Non Finnish (NFE) AF: 0.344 AC: 381927 AN: 1111266

Other (OTH) AF: 0.346 AC: 20909 AN: 60370

GnomAD4 genome AF: 0.388 AC: 58985 AN: 152012 Hom.: 12081 Cov.: 32 AF XY: 0.388 AC XY: 28820 AN XY: 74300

African (AFR) AF: 0.504 AC: 20900 AN: 41480

American (AMR) AF: 0.399 AC: 6088 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1220 AN: 3468

East Asian (EAS) AF: 0.179 AC: 926 AN: 5166

South Asian (SAS) AF: 0.261 AC: 1258 AN: 4826

European-Finnish (FIN) AF: 0.391 AC: 4136 AN: 10570

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23163 AN: 67942

Other (OTH) AF: 0.382 AC: 807 AN: 2110

Alfa AF: 0.359 Hom.: 32130

Bravo AF: 0.394

Asia WGS AF: 0.288 AC: 1004 AN: 3478

EpiCase AF: 0.335

EpiControl AF: 0.345

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

- -

Jan 13, 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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	-1.0
CADD	Benign	0.13
DANN	Benign	0.21
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775883; hg19: chr19-55451797; COSMIC: COSV60172253; COSMIC: COSV60172253;