chr19-54939682-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127255.2(NLRP7):c.1137G>C(p.Lys379Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,612,818 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K379K) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0039 ( 12 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 55 hom. )

Consequence

NLRP7
NM_001127255.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -6.88

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070764422).

BP6

Variant 19-54939682-C-G is Benign according to our data. Variant chr19-54939682-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97715.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Benign=2}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00389 (591/152008) while in subpopulation EAS AF = 0.00857 (44/5132). AF 95% confidence interval is 0.00656. There are 12 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NLRP7	NM_001127255.2 link	c.1137G>C	p.Lys379Asn	missense_variant	Exon 4 of 11	NP_001120727.1	Q8WX94-3
NLRP7	NM_001405531.1 link	c.1137G>C	p.Lys379Asn	missense_variant	Exon 6 of 13	NP_001392460.1
NLRP7	NM_139176.4 link	c.1137G>C	p.Lys379Asn	missense_variant	Exon 4 of 11	NP_631915.2	Q8WX94-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6 link	c.1137G>C	p.Lys379Asn	missense_variant	Exon 4 of 11	1		ENSP00000468706.1		Q8WX94-3

Frequencies

GnomAD3 genomes

AF:

0.00389

AC:

591

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00855

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00501

AC:

1248

AN:

249060

AF XY:

0.00483

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00190

Gnomad EAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.0400

Gnomad NFE exome

AF:

0.000989

Gnomad OTH exome

AF:

0.00312

GnomAD4 exome

AF:

0.00225

AC:

3290

AN:

1460810

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1639

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

AC:

AN:

33444

Gnomad4 AMR exome

AF:

0.000246

AC:

AN:

44684

Gnomad4 ASJ exome

AF:

0.00180

AC:

AN:

26130

Gnomad4 EAS exome

AF:

0.0161

AC:

638

AN:

39700

Gnomad4 SAS exome

AF:

0.000650

AC:

AN:

86214

Gnomad4 FIN exome

AF:

0.0379

AC:

2017

AN:

53216

Gnomad4 NFE exome

AF:

0.000358

AC:

398

AN:

1111932

Gnomad4 Remaining exome

AF:

0.00196

AC:

118

AN:

60320

Heterozygous variant carriers

260

521

781

1042

1302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00389

AC:

591

AN:

152008

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

435

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000723

AC:

0.000072317

AN:

0.000072317

Gnomad4 AMR

AF:

0.000197

AC:

0.000196618

AN:

0.000196618

Gnomad4 ASJ

AF:

0.00173

AC:

0.00172811

AN:

0.00172811

Gnomad4 EAS

AF:

0.00857

AC:

0.00857366

AN:

0.00857366

Gnomad4 SAS

AF:

0.00104

AC:

0.00103993

AN:

0.00103993

Gnomad4 FIN

AF:

0.0441

AC:

0.0440732

AN:

0.0440732

Gnomad4 NFE

AF:

0.000854

AC:

0.000853544

AN:

0.000853544

Gnomad4 OTH

AF:

0.00238

AC:

0.00237643

AN:

0.00237643

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

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:

0.00115

Hom.:

426

ExAC

AF:

0.00446

AC:

541

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hydatidiform mole, recurrent, 1

Uncertain:1Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Prostate cancer

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NLRP7: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0060

DANN

Benign

0.94

DEOGEN2

Benign

0.17

T;.;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0075

MetaRNN

Benign

0.0071

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

L;L;L;L;L

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.4

D;D;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.057

T;T;.;.;.

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0090

B;B;B;.;.

Vest4

0.47

MVP

0.12

MPC

0.29

ClinPred

0.0064

GERP RS

-2.5

Varity_R

0.11

gMVP

0.64

Mutation Taster

=99/1

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over