3-101849914-C-T

Position:

• chr3-101849914-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031419.4(NFKBIZ):​c.286C>T​(p.Pro96Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000788 in 1,268,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: NFKBIZ NM_031419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12826416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIZ	NM_031419.4	c.286C>T	p.Pro96Ser	missense_variant	1/12	ENST00000326172.9	NP_113607.1
NFKBIZ	NM_001005474.3	c.-11-2171C>T		intron_variant			NP_001005474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.286C>T	p.Pro96Ser	missense_variant	1/12	1	NM_031419.4	ENSP00000325663.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.88e-7 AC: 1 AN: 1268528 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 621592

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.73e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 30, 2024

The c.286C>T (p.P96S) alteration is located in exon 1 (coding exon 1) of the NFKBIZ gene. This alteration results from a C to T substitution at nucleotide position 286, causing the proline (P) at amino acid position 96 to be replaced by a serine (S). 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	0.081
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T;.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;N;N
REVEL	Benign	0.057
Sift	Benign	0.19	T;D;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.013, 0.020	.;B;B
Vest4		0.10, 0.091
MutPred		0.17		Gain of phosphorylation at P96 (P = 0.0101);Gain of phosphorylation at P96 (P = 0.0101);Gain of phosphorylation at P96 (P = 0.0101);
MVP		0.15
MPC		0.24
ClinPred		0.27	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.066
gMVP		0.096

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-101568758;