3-101849775-C-G

Variant names:

• chr3-101849775-C-G
• NM_031419.4:c.147C>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.147C>G​(p.Asp49Glu) 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. 13/21 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: 0.123

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=0.099411696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIZ	NM_031419.4	c.147C>G	p.Asp49Glu	missense_variant	Exon 1 of 12	ENST00000326172.9	NP_113607.1
NFKBIZ	NM_001005474.3	c.-11-2310C>G		intron_variant	Intron 2 of 12		NP_001005474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9	c.147C>G	p.Asp49Glu	missense_variant	Exon 1 of 12	1	NM_031419.4	ENSP00000325663.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.147C>G (p.D49E) alteration is located in exon 1 (coding exon 1) of the NFKBIZ gene. This alteration results from a C to G substitution at nucleotide position 147, causing the aspartic acid (D) at amino acid position 49 to be replaced by a glutamic acid (E). 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	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.056	T;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	.;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0020, 0.0090	.;B;B
Vest4		0.047, 0.063
MutPred		0.21		Gain of glycosylation at P45 (P = 0.1478);Gain of glycosylation at P45 (P = 0.1478);Gain of glycosylation at P45 (P = 0.1478);
MVP		0.19
MPC		0.23
ClinPred		0.082	T
GERP RS		1.9
Varity_R		0.052
gMVP		0.076

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: chr3-101568619;