3-101849911-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (6 hom.)
• Consequence: NFKBIZ NM_031419.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.785

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]

ACMG classification

Verdict is Benign. Variant got -10 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 criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIZ	NM_031419.4	c.283C>A	p.Gln95Lys	missense_variant	1/12	ENST00000326172.9
NFKBIZ	NM_001005474.3	c.-11-2174C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.283C>A	p.Gln95Lys	missense_variant	1/12	1	NM_031419.4	P4

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152186 Hom.: 0 Cov.: 32

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: 65 AN: 30050 Hom.: 0 AF XY: 0.00248 AC XY: 44 AN XY: 17728

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.: 6 Cov.: 31 AF XY: 0.00384 AC XY: 2386 AN XY: 621896

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.: 0 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74486

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.: 0

Bravo AF: 0.00239

ExAC AF: 0.000396 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NFKBIZ-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2020

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.022	T;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs779117101; hg19: chr3-101568755; COSMIC: COSV58200566; COSMIC: COSV58200566;