3-101853377-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031419.4(NFKBIZ):c.851C>T(p.Ala284Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,614,170 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (1 hom.)
• Consequence: NFKBIZ NM_031419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02108121).
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIZ	NM_031419.4	c.851C>T	p.Ala284Val	missense_variant	5/12	ENST00000326172.9
NFKBIZ	NM_001005474.3	c.551C>T	p.Ala184Val	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.851C>T	p.Ala284Val	missense_variant	5/12	1	NM_031419.4	P4
NFKBIZ	ENST00000394054.6	c.551C>T	p.Ala184Val	missense_variant	6/13	1		A2
NFKBIZ	ENST00000483180.5	c.551C>T	p.Ala184Val	missense_variant	5/11	5
NFKBIZ	ENST00000326151.9	c.708+143C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251462 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135904

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461892 Hom.: 1 Cov.: 33 AF XY: 0.000121 AC XY: 88 AN XY: 727246

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74452

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.851C>T (p.A284V) alteration is located in exon 5 (coding exon 5) of the NFKBIZ gene. This alteration results from a C to T substitution at nucleotide position 851, causing the alanine (A) at amino acid position 284 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0043
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.049	.;.;B
Vest4		0.13, 0.10
MVP		0.59
MPC		0.27
ClinPred		0.34	T
GERP RS		5.6
Varity_R		0.061
gMVP		0.28

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: rs146210819; hg19: chr3-101572221;