3-101853528-T-G

Variant summary

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

The NM_031419.4(NFKBIZ):c.1002T>G(p.Phe334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: NFKBIZ NM_031419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.369

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 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=0.14690834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIZ	NM_031419.4	c.1002T>G	p.Phe334Leu	missense_variant	5/12	ENST00000326172.9
NFKBIZ	NM_001005474.3	c.702T>G	p.Phe234Leu	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.1002T>G	p.Phe334Leu	missense_variant	5/12	1	NM_031419.4	P4
NFKBIZ	ENST00000394054.6	c.702T>G	p.Phe234Leu	missense_variant	6/13	1		A2
NFKBIZ	ENST00000483180.5	c.702T>G	p.Phe234Leu	missense_variant	5/11	5
NFKBIZ	ENST00000326151.9	c.709-73T>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Nov 03, 2023

The c.1002T>G (p.F334L) alteration is located in exon 5 (coding exon 5) of the NFKBIZ gene. This alteration results from a T to G substitution at nucleotide position 1002, causing the phenylalanine (F) at amino acid position 334 to be replaced by a leucine (L). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	14
Dann	Benign	0.94
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.032	D;D;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.10	.;.;B
Vest4		0.17, 0.23
MutPred		0.32		.;.;Gain of catalytic residue at F334 (P = 0.0969);
MVP		0.42
MPC		0.27
ClinPred		0.31	T
GERP RS		-0.51
Varity_R		0.12
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-101572372;