NM_031419.4:c.430-32A>G

Variant names:

• chr3-101852706-A-G
• rs587555
• NM_031419.4:c.430-32A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• Publications: 11 publications found

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

ACMG classification

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	c.430-32A>G		intron_variant	Intron 2 of 11	ENST00000326172.9	NP_113607.1
NFKBIZ	NM_001005474.3	c.130-32A>G		intron_variant	Intron 3 of 12		NP_001005474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.430-32A>G		intron_variant	Intron 2 of 11	1	NM_031419.4	ENSP00000325663.5

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86343 AN: 151942 Hom.: 25651 Cov.: 32

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

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.: 23 AF XY: 0.646 AC XY: 446508 AN XY: 690728

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

GnomAD4 genome AF: 0.568 AC: 86414 AN: 152062 Hom.: 25670 Cov.: 32 AF XY: 0.561 AC XY: 41719 AN XY: 74324

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

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
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)

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

Other links and lift over

dbSNP: rs587555; hg19: chr3-101571550; COSMIC: COSV58200254; COSMIC: COSV58200254;