ENST00000588756.5:c.3082A>G

Variant names:

• chr19-54923772-T-C
• rs7256020
• ENST00000588756.5:c.3082A>G

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.3082A>G​(p.Thr1028Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,772 control chromosomes in the GnomAD database, including 196 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1028M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (100 hom.)
• Consequence: NLRP7 ENST00000588756.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.774

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003714949).
• BP6: Variant 19-54923772-T-C is Benign according to our data. Variant chr19-54923772-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 893569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54923772-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.3082A>G	p.Thr1028Ala	missense_variant	Exon 11 of 11		NP_001120727.1
NLRP7	NM_001405531.1	c.3082A>G	p.Thr1028Ala	missense_variant	Exon 13 of 13		NP_001392460.1
NLRP7	NM_139176.4	c.2998A>G	p.Thr1000Ala	missense_variant	Exon 11 of 11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.3082A>G	p.Thr1028Ala	missense_variant	Exon 11 of 11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3221 AN: 152122 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00977

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00598 AC: 1500 AN: 251010 Hom.: 42 AF XY: 0.00431 AC XY: 585 AN XY: 135740

Gnomad AFR exome AF: 0.0754

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000424

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00243 AC: 3549 AN: 1461532 Hom.: 100 Cov.: 31 AF XY: 0.00213 AC XY: 1550 AN XY: 727062

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.0212 AC: 3227 AN: 152240 Hom.: 96 Cov.: 32 AF XY: 0.0203 AC XY: 1508 AN XY: 74450

Gnomad4 AFR AF: 0.0722

Gnomad4 AMR AF: 0.00976

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00909 Hom.: 27

Bravo AF: 0.0249

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0731 AC: 322

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00687 AC: 834

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.026
DANN	Benign	0.17
DEOGEN2	Benign	0.017	T;.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
MetaRNN	Benign	0.0037	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.61	N;N;.;.;.
REVEL	Benign	0.053
Sift	Benign	0.26	T;T;.;.;.
Sift4G	Benign	0.41	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.12
MVP		0.16
MPC		0.24
ClinPred		0.00096	T
GERP RS		-2.7
Varity_R		0.028
gMVP		0.080

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: rs7256020; hg19: chr19-55435140;