3-101857058-C-T

Variant names:

• chr3-101857058-C-T
• rs7628891
• NM_031419.4:c.1825-15C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_031419.4(NFKBIZ):​c.1825-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,539,284 control chromosomes in the GnomAD database, including 600 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.

• Frequency:
  • Genomes: 𝑓 0.020 (52 hom., cov: 31)
  • Exomes 𝑓: 0.022 (548 hom.)
• Consequence: NFKBIZ NM_031419.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.411
• Publications: 6 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: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0196 (2955/150706) while in subpopulation NFE AF = 0.0259 (1755/67692). AF 95% confidence interval is 0.0249. There are 52 homozygotes in GnomAd4. There are 1547 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2955 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIZ	NM_031419.4	c.1825-15C>T		intron_variant	Intron 9 of 11	ENST00000326172.9	NP_113607.1
NFKBIZ	NM_001005474.3	c.1525-15C>T		intron_variant	Intron 10 of 12		NP_001005474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.1825-15C>T		intron_variant	Intron 9 of 11	1	NM_031419.4	ENSP00000325663.5

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2955 AN: 150590 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.00981

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00626

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0164

GnomAD2 exomes AF: 0.0208 AC: 4859 AN: 233430 AF XY: 0.0209

Gnomad AFR exome AF: 0.00341

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.0793

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0225 AC: 31217 AN: 1388578 Hom.: 548 Cov.: 28 AF XY: 0.0220 AC XY: 15171 AN XY: 690548

African (AFR) AF: 0.00353 AC: 110 AN: 31156

American (AMR) AF: 0.00576 AC: 230 AN: 39920

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 263 AN: 24994

East Asian (EAS) AF: 0.0000515 AC: 2 AN: 38842

South Asian (SAS) AF: 0.00633 AC: 511 AN: 80698

European-Finnish (FIN) AF: 0.0797 AC: 4182 AN: 52500

Middle Eastern (MID) AF: 0.00704 AC: 39 AN: 5538

European-Non Finnish (NFE) AF: 0.0234 AC: 24718 AN: 1057468

Other (OTH) AF: 0.0202 AC: 1162 AN: 57462

GnomAD4 genome AF: 0.0196 AC: 2955 AN: 150706 Hom.: 52 Cov.: 31 AF XY: 0.0211 AC XY: 1547 AN XY: 73438

African (AFR) AF: 0.00301 AC: 124 AN: 41164

American (AMR) AF: 0.00876 AC: 133 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00981 AC: 34 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00627 AC: 30 AN: 4784

European-Finnish (FIN) AF: 0.0840 AC: 839 AN: 9988

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1755 AN: 67692

Other (OTH) AF: 0.0162 AC: 34 AN: 2100

Alfa AF: 0.0281 Hom.: 10

Bravo AF: 0.0131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.41
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: rs7628891; hg19: chr3-101575902; COSMIC: COSV58199993;