Genetic Variant NFKBIZ:p.Ala81Val (chr3-101849870-C-T) – 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.242C>T(p.Ala81Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,456,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

NFKBIZ
NM_031419.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.04

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066841245).

BP6

Variant 3-101849870-C-T is Benign according to our data. Variant chr3-101849870-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3036671.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIZ	NM_031419.4 link	c.242C>T	p.Ala81Val	missense_variant	Exon 1 of 12	ENST00000326172.9	NP_113607.1	Q9BYH8-1
NFKBIZ	NM_001005474.3 link	c.-11-2215C>T		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.242C>T	p.Ala81Val	missense_variant	Exon 1 of 12	1	NM_031419.4	ENSP00000325663.5		Q9BYH8-1

Frequencies

GnomAD3 genomes

AF:

0.000960

AC:

146

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000663

AC:

AN:

60330

Hom.:

AF XY:

0.0000565

AC XY:

AN XY:

35418

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000552

AC:

AN:

1304120

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

642498

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.0000452

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000142

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000259

GnomAD4 genome

AF:

0.000966

AC:

147

AN:

152182

Hom.:

Cov.:

AF XY:

0.000914

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00349

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000950

Hom.:

Bravo

AF:

0.00103

ExAC

AF:

0.0000383

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NFKBIZ-related disorder

Benign:1

Jun 05, 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

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

T;.;T

Eigen

Benign

-0.016

Eigen_PC

Benign

0.061

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.80

T;T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.8

.;L;L

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.9

D;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0060

D;D;D

Sift4G

Pathogenic

0.0

D;T;T

Polyphen

0.83, 0.73

.;P;P

Vest4

0.23, 0.15

MutPred

0.30

Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);

MVP

0.36

MPC

0.23

ClinPred

0.17

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.10

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