19-54939864-C-T

Variant names:

• chr19-54939864-C-T
• rs775882
• NM_001127255.2:c.955G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127255.2(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. 16/21 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 NM_001127255.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.31
• Publications: 28 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 -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 VariationId is 330176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	ENST00000592784.6	NP_001120727.1

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	NM_001127255.2	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

GnomAD2 exomes AF: 0.241 AC: 60578 AN: 251130 AF XY: 0.233

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 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

African (AFR) AF: 0.469 AC: 15699 AN: 33476

American (AMR) AF: 0.322 AC: 14381 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5817 AN: 26134

East Asian (EAS) AF: 0.173 AC: 6869 AN: 39698

South Asian (SAS) AF: 0.229 AC: 19780 AN: 86254

European-Finnish (FIN) AF: 0.213 AC: 11387 AN: 53408

Middle Eastern (MID) AF: 0.248 AC: 1433 AN: 5768

European-Non Finnish (NFE) AF: 0.216 AC: 239885 AN: 1111804

Other (OTH) AF: 0.234 AC: 14146 AN: 60390

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

African (AFR) AF: 0.463 AC: 19177 AN: 41430

American (AMR) AF: 0.322 AC: 4906 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 723 AN: 3470

East Asian (EAS) AF: 0.172 AC: 888 AN: 5164

South Asian (SAS) AF: 0.228 AC: 1099 AN: 4820

European-Finnish (FIN) AF: 0.210 AC: 2220 AN: 10576

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14354 AN: 67954

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.226 Hom.: 10733

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
PhyloP100		-1.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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