rs10418277

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.00501

AC:

1248

AN:

249060

Hom.:

AF XY:

0.00483

AC XY:

652

AN XY:

135116

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 SAS exome

AF:

0.000621

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

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.0161

Gnomad4 SAS exome

AF:

0.000650

Gnomad4 FIN exome

AF:

0.0379

Gnomad4 NFE exome

AF:

0.000358

Gnomad4 OTH exome

AF:

0.00196

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

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00857

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0441

Gnomad4 NFE

AF:

0.000854

Gnomad4 OTH

AF:

0.00238

Alfa

AF:

0.00179

Hom.:

322

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

NLRP7: BP4, BS1, BS2 -

Malignant tumor of prostate

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

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