Genetic Variant NLRP11:p.Ser1025Leu (chr19-55785653-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001394894.2(NLRP11):c.3074C>T(p.Ser1025Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 1,613,840 control chromosomes in the GnomAD database, including 79 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 70 hom. )

Consequence

NLRP11
NM_001394894.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0650

Variant links:

Genes affected

NLRP11 (HGNC:22945): (NLR family pyrin domain containing 11) This gene is a member of the the NOD-like receptor protein (NLRP) gene family and encodes a protein with an N-terminal pyrin death (PYD) domain and nucleoside triphosphate hydrolase (NACHT) domain and a C-terminal leucine-rich repeats (LRR) region. This gene has been shown to regulate caspases in the proinflammatory signal transduction pathway and, based on studies of other members of the NLRP gene family with similar domain structure, is predicted to form part of the multiprotein inflammasome complex. Alternative splicing produces multiple transcript variants encoding distince isoforms. [provided by RefSeq, May 2017]

NLRP11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074005127).

BP6

Variant 19-55785653-G-A is Benign according to our data. Variant chr19-55785653-G-A is described in ClinVar as [Benign]. Clinvar id is 789353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP11	NM_001394894.2 link	c.3074C>T	p.Ser1025Leu	missense_variant	Exon 10 of 10	ENST00000589093.6	NP_001381823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP11	ENST00000589093.6 link	c.3074C>T	p.Ser1025Leu	missense_variant	Exon 10 of 10	1	NM_001394894.2	ENSP00000466285.1		P59045-1

Frequencies

GnomAD3 genomes

AF:

0.00693

AC:

1054

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00673

AC:

1690

AN:

251286

AF XY:

0.00705

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.00794

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.00865

AC:

12648

AN:

1461560

Hom.:

Cov.:

AF XY:

0.00843

AC XY:

6131

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

AC:

AN:

33466

Gnomad4 AMR exome

AF:

0.00637

AC:

285

AN:

44720

Gnomad4 ASJ exome

AF:

0.00735

AC:

192

AN:

26132

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39696

Gnomad4 SAS exome

AF:

0.00147

AC:

127

AN:

86224

Gnomad4 FIN exome

AF:

0.00262

AC:

140

AN:

53416

Gnomad4 NFE exome

AF:

0.0102

AC:

11367

AN:

1111756

Gnomad4 Remaining exome

AF:

0.00745

AC:

450

AN:

60384

Heterozygous variant carriers

558

1116

1674

2232

2790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

400

800

1200

1600

2000

<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:

0.00692

AC:

1054

AN:

152280

Hom.:

Cov.:

AF XY:

0.00625

AC XY:

465

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00219

AC:

0.00218961

AN:

0.00218961

Gnomad4 AMR

AF:

0.00765

AC:

0.00765206

AN:

0.00765206

Gnomad4 ASJ

AF:

0.00806

AC:

0.00806452

AN:

0.00806452

Gnomad4 EAS

AF:

0.000193

AC:

0.000192976

AN:

0.000192976

Gnomad4 SAS

AF:

0.00145

AC:

0.00144988

AN:

0.00144988

Gnomad4 FIN

AF:

0.00226

AC:

0.00226287

AN:

0.00226287

Gnomad4 NFE

AF:

0.0108

AC:

0.0108344

AN:

0.0108344

Gnomad4 OTH

AF:

0.00758

AC:

0.00757576

AN:

0.00757576

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00983

Hom.:

Bravo

AF:

0.00707

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00676

AC:

821

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

2.9

DANN

Benign

0.96

DEOGEN2

Benign

0.0042

.;.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.69

.;.;N

PrimateAI

Benign

0.39

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;P

Vest4

0.10

MVP

0.70

ClinPred

0.0044

GERP RS

-1.5

Varity_R

0.049

gMVP

0.066

Mutation Taster

=100/0

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