Genetic Variant NM_001127255.2:c.2156C>T (chr19-54936405-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001127255.2(NLRP7):c.2156C>T(p.Ala719Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,074 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A719T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 5 hom. )

Consequence

NLRP7
NM_001127255.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 3.01

Publications

13 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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001127255.2

BP4

Computational evidence support a benign effect (MetaRNN=0.053436667).

BP6

Variant 19-54936405-G-A is Benign according to our data. Variant chr19-54936405-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97747.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00115 (1685/1461766) while in subpopulation MID AF = 0.017 (98/5768). AF 95% confidence interval is 0.0143. There are 5 homozygotes in GnomAdExome4. There are 801 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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.2156C>T	p.Ala719Val	missense	Exon 6 of 11	NP_001120727.1
NLRP7	NM_001405531.1		c.2156C>T	p.Ala719Val	missense	Exon 8 of 13	NP_001392460.1
NLRP7	NM_139176.4		c.2072C>T	p.Ala691Val	missense	Exon 6 of 11	NP_631915.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.2156C>T	p.Ala719Val	missense	Exon 6 of 11	ENSP00000468706.1
NLRP7	ENST00000588756.5	TSL:1	c.2156C>T	p.Ala719Val	missense	Exon 8 of 13	ENSP00000467123.1
NLRP7	ENST00000340844.6	TSL:1	c.2156C>T	p.Ala719Val	missense	Exon 6 of 10	ENSP00000339491.2

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00105

AC:

264

AN:

251356

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00115

AC:

1685

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

801

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00126

AC:

1405

AN:

1111898

Other (OTH)

AF:

0.00113

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000991

AC:

151

AN:

152308

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41576

American (AMR)

AF:

0.000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

68042

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00133

Hom.:

Bravo

AF:

0.000937

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00119

AC:

144

EpiCase

AF:

0.00131

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hydatidiform mole, recurrent, 1 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.070

M_CAP

Benign

0.0087

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

PhyloP100

3.0

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

Sift4G

Benign

0.095

Polyphen

0.95

Vest4

0.52

MVP

0.52

MPC

0.39

ClinPred

0.034

GERP RS

0.90

Varity_R

0.11

gMVP

0.18

Mutation Taster

=97/3

polymorphism

(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