rs7256020

Variant names:

• chr19-54923772-T-C
• rs7256020
• NM_001127255.2:c.3082A>G

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.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. 16/21 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 NM_001127255.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.774
• Publications: 3 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]

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

Our verdict: Benign. The variant received -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 VariationId is 893569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127255.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	NM_001127255.2	MANE Select	c.3082A>G	p.Thr1028Ala	missense	Exon 11 of 11	NP_001120727.1	Q8WX94-3
	NLRP7	NM_001405531.1		c.3082A>G	p.Thr1028Ala	missense	Exon 13 of 13	NP_001392460.1	Q8WX94-3
	NLRP7	NM_139176.4		c.2998A>G	p.Thr1000Ala	missense	Exon 11 of 11	NP_631915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.3082A>G	p.Thr1028Ala	missense	Exon 11 of 11	ENSP00000468706.1	Q8WX94-3
	NLRP7	ENST00000588756.5	TSL:1	c.3082A>G	p.Thr1028Ala	missense	Exon 13 of 13	ENSP00000467123.1	Q8WX94-3
	NLRP7	ENST00000340844.6	TSL:1	c.2911A>G	p.Thr971Ala	missense	Exon 10 of 10	ENSP00000339491.2	Q8WX94-1

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

GnomAD2 exomes AF: 0.00598 AC: 1500 AN: 251010 AF XY: 0.00431

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 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

African (AFR) AF: 0.0759 AC: 2541 AN: 33470

American (AMR) AF: 0.00528 AC: 236 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00745 AC: 41 AN: 5500

European-Non Finnish (NFE) AF: 0.000280 AC: 311 AN: 1112000

Other (OTH) AF: 0.00537 AC: 324 AN: 60348

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

African (AFR) AF: 0.0722 AC: 2999 AN: 41534

American (AMR) AF: 0.00976 AC: 149 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68018

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0149 Hom.: 55

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hydatidiform mole, recurrent, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.77
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.053
Sift	Benign	0.26	T
Sift4G	Benign	0.41	T
Polyphen		0.0	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
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: rs7256020; hg19: chr19-55435140;