3-101853350-G-C

Position:

• chr3-101853350-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031419.4(NFKBIZ):​c.824G>C​(p.Arg275Thr) 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. 16/21 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: 2.62

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04753697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIZ	NM_031419.4	c.824G>C	p.Arg275Thr	missense_variant	5/12	ENST00000326172.9	NP_113607.1
NFKBIZ	NM_001005474.3	c.524G>C	p.Arg175Thr	missense_variant	6/13		NP_001005474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.824G>C	p.Arg275Thr	missense_variant	5/12	1	NM_031419.4	ENSP00000325663.5
NFKBIZ	ENST00000394054.6	c.524G>C	p.Arg175Thr	missense_variant	6/13	1		ENSP00000377618.2
NFKBIZ	ENST00000483180.5	c.524G>C	p.Arg175Thr	missense_variant	5/11	5		ENSP00000419800.1
NFKBIZ	ENST00000326151.9	c.708+116G>C		intron_variant		2		ENSP00000325593.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.69
DEOGEN2	Benign	0.11	.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.025	D;D;D
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.23, 0.20
MutPred		0.23		.;.;Loss of MoRF binding (P = 0.0933);
MVP		0.12
MPC		0.34
ClinPred		0.085	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.19

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: rs1312913255; hg19: chr3-101572194;