dbSNP rs587555: NFKBIZ:c.430-32A>G (chr3-101852706-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_031419.4(NFKBIZ):c.430-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,532,600 control chromosomes in the GnomAD database, including 322,054 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.57 ( 25670 hom., cov: 32)

Exomes 𝑓: 0.65 ( 296384 hom. )

Consequence

NFKBIZ
NM_031419.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0260

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NFKBIZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIZ	NM_031419.4 link	c.430-32A>G		intron_variant	Intron 2 of 11	ENST00000326172.9	NP_113607.1	Q9BYH8-1
NFKBIZ	NM_001005474.3 link	c.130-32A>G		intron_variant	Intron 3 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.430-32A>G		intron_variant	Intron 2 of 11	1	NM_031419.4	ENSP00000325663.5		Q9BYH8-1

Frequencies

GnomAD3 genomes

AF:

0.568

AC:

86343

AN:

151942

Hom.:

25651

Cov.:

show subpopulations

Gnomad AFR

AF:

0.397

Gnomad AMI

AF:

0.641

Gnomad AMR

AF:

0.675

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.465

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.546

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.660

Gnomad OTH

AF:

0.586

GnomAD2 exomes

AF:

0.617

AC:

146567

AN:

237664

AF XY:

0.614

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.754

Gnomad ASJ exome

AF:

0.612

Gnomad EAS exome

AF:

0.484

Gnomad FIN exome

AF:

0.544

Gnomad NFE exome

AF:

0.666

Gnomad OTH exome

AF:

0.630

GnomAD4 exome

AF:

0.651

AC:

898175

AN:

1380538

Hom.:

296384

Cov.:

AF XY:

0.646

AC XY:

446508

AN XY:

690728

show subpopulations

African (AFR)

AF:

0.380

AC:

11838

AN:

31114

American (AMR)

AF:

0.744

AC:

30338

AN:

40790

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

15355

AN:

24952

East Asian (EAS)

AF:

0.459

AC:

18033

AN:

39282

South Asian (SAS)

AF:

0.532

AC:

43450

AN:

81624

European-Finnish (FIN)

AF:

0.550

AC:

29154

AN:

53026

Middle Eastern (MID)

AF:

0.584

AC:

2611

AN:

4468

European-Non Finnish (NFE)

AF:

0.679

AC:

711312

AN:

1047738

Other (OTH)

AF:

0.627

AC:

36084

AN:

57544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

14249

28498

42747

56996

71245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17864

35728

53592

71456

89320

<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:

0.568

AC:

86414

AN:

152062

Hom.:

25670

Cov.:

AF XY:

0.561

AC XY:

41719

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.397

AC:

16456

AN:

41450

American (AMR)

AF:

0.676

AC:

10334

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2134

AN:

3472

East Asian (EAS)

AF:

0.465

AC:

2406

AN:

5174

South Asian (SAS)

AF:

0.512

AC:

2462

AN:

4812

European-Finnish (FIN)

AF:

0.546

AC:

5768

AN:

10570

Middle Eastern (MID)

AF:

0.548

AC:

161

AN:

294

European-Non Finnish (NFE)

AF:

0.660

AC:

44868

AN:

67980

Other (OTH)

AF:

0.590

AC:

1244

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1829

3659

5488

7318

9147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<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:

0.603

Hom.:

5142

Bravo

AF:

0.578

Asia WGS

AF:

0.473

AC:

1646

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.80

(source)

DANN

Benign

0.69

PhyloP100

0.026

BranchPoint Hunter

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over