Genetic Variant NLRP7:p.Ala925Ala (chr19-54930534-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. A925A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.55 ( 23596 hom., cov: 31)

Exomes 𝑓: 0.56 ( 231219 hom. )

Consequence

NLRP7
NM_001127255.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.83

Publications

19 publications found

Variant links:

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 links:

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]

NCR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.033).

BP6

Variant 19-54930534-T-C is Benign according to our data. Variant chr19-54930534-T-C is described in ClinVar as Benign. ClinVar VariationId is 330156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

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

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

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.2775A>G	p.Ala925Ala	synonymous	Exon 9 of 11	ENSP00000468706.1
NLRP7	ENST00000588756.5	TSL:1	c.2775A>G	p.Ala925Ala	synonymous	Exon 11 of 13	ENSP00000467123.1
NLRP7	ENST00000340844.6	TSL:1	c.2775A>G	p.Ala925Ala	synonymous	Exon 9 of 10	ENSP00000339491.2

Frequencies

GnomAD3 genomes

AF:

0.554

AC:

84170

AN:

151810

Hom.:

23574

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.588

AC:

147847

AN:

251404

AF XY:

0.589

show subpopulations

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 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.:

AF XY:

0.565

AC XY:

409176

AN XY:

724438

show subpopulations

African (AFR)

AF:

0.511

AC:

17044

AN:

33356

American (AMR)

AF:

0.639

AC:

28586

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.628

AC:

16367

AN:

26082

East Asian (EAS)

AF:

0.719

AC:

28507

AN:

39670

South Asian (SAS)

AF:

0.637

AC:

54859

AN:

86144

European-Finnish (FIN)

AF:

0.550

AC:

29365

AN:

53374

Middle Eastern (MID)

AF:

0.620

AC:

3569

AN:

5758

European-Non Finnish (NFE)

AF:

0.546

AC:

604249

AN:

1106172

Other (OTH)

AF:

0.573

AC:

34512

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

16830

33659

50489

67318

84148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17078

34156

51234

68312

85390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.554

AC:

84235

AN:

151928

Hom.:

23596

Cov.:

AF XY:

0.558

AC XY:

41416

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.518

AC:

21480

AN:

41438

American (AMR)

AF:

0.578

AC:

8808

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.626

AC:

2169

AN:

3464

East Asian (EAS)

AF:

0.718

AC:

3688

AN:

5140

South Asian (SAS)

AF:

0.635

AC:

3059

AN:

4818

European-Finnish (FIN)

AF:

0.553

AC:

5841

AN:

10564

Middle Eastern (MID)

AF:

0.582

AC:

170

AN:

292

European-Non Finnish (NFE)

AF:

0.553

AC:

37599

AN:

67950

Other (OTH)

AF:

0.548

AC:

1159

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1914

3827

5741

7654

9568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.558

Hom.:

35153

Bravo

AF:

0.554

Asia WGS

AF:

0.619

AC:

2154

AN:

3478

EpiCase

AF:

0.555

EpiControl

AF:

0.552

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hydatidiform mole, recurrent, 1 (3)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.75

(source)

DANN

Benign

0.34

PhyloP100

-2.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over