Genetic Variant NFKBIZ:p.Gln95Lys (chr3-101849911-C-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_031419.4(NFKBIZ):c.283C>A(p.Gln95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,421,284 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 6 hom. )

Consequence

NFKBIZ
NM_031419.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.785

Variant links:

Genes affected

NFKBIZ (HGNC:29805): (NFKB inhibitor zeta) This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-B proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NFKBIZ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035072267).

BP6

Variant 3-101849911-C-A is Benign according to our data. Variant chr3-101849911-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3043308.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIZ	NM_031419.4 link	c.283C>A	p.Gln95Lys	missense_variant	Exon 1 of 12	ENST00000326172.9	NP_113607.1	Q9BYH8-1
NFKBIZ	NM_001005474.3 link	c.-11-2174C>A		intron_variant	Intron 2 of 12		NP_001005474.1	Q9BYH8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9 link	c.283C>A	p.Gln95Lys	missense_variant	Exon 1 of 12	1	NM_031419.4	ENSP00000325663.5		Q9BYH8-1

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

366

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00372

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00216

AC:

AN:

30050

Hom.:

AF XY:

0.00248

AC XY:

AN XY:

17728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000746

Gnomad ASJ exome

AF:

0.000438

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000827

Gnomad FIN exome

AF:

0.00108

Gnomad NFE exome

AF:

0.00470

Gnomad OTH exome

AF:

0.00546

GnomAD4 exome

AF:

0.00393

AC:

4991

AN:

1268984

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

2386

AN XY:

621896

show subpopulations

Gnomad4 AFR exome

AF:

0.000517

Gnomad4 AMR exome

AF:

0.000574

Gnomad4 ASJ exome

AF:

0.000357

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00162

Gnomad4 NFE exome

AF:

0.00459

Gnomad4 OTH exome

AF:

0.00216

GnomAD4 genome

AF:

0.00240

AC:

366

AN:

152300

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.00372

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00323

Hom.:

Bravo

AF:

0.00239

ExAC

AF:

0.000396

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NFKBIZ-related disorder

Benign:1

Jun 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.022

T;.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.64

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0020, 0.0010

.;B;B

Vest4

0.050, 0.052

MVP

0.27

MPC

0.30

ClinPred

0.027

GERP RS

1.2

Varity_R

0.15

gMVP

0.042

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