Variant 6-44265087-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004556.3(NFKBIE):c.260G>T(p.Gly87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,559,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

NFKBIE
NM_004556.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.215

Variant links:

Genes affected

NFKBIE (HGNC:7799): (NFKB inhibitor epsilon) The protein encoded by this gene binds to components of NF-kappa-B, trapping the complex in the cytoplasm and preventing it from activating genes in the nucleus. Phosphorylation of the encoded protein targets it for destruction by the ubiquitin pathway, which activates NF-kappa-B by making it available to translocate to the nucleus. [provided by RefSeq, Sep 2011]

NFKBIE links:

POLR1C (HGNC:):

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.034487814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIE	NM_004556.3 linkuse as main transcript	c.260G>T	p.Gly87Val	missense_variant	1/6	ENST00000619360.6
POLR1C	NM_001318876.2 linkuse as main transcript	c.946-176803C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NFKBIE	ENST00000619360.6 linkuse as main transcript	c.260G>T	p.Gly87Val	missense_variant	1/6	1	NM_004556.3	P1
NFKBIE	ENST00000275015.9 linkuse as main transcript	c.677G>T	p.Gly226Val	missense_variant	1/6	1
NFKBIE	ENST00000477930.2 linkuse as main transcript	c.260G>T	p.Gly87Val	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000166

AC:

AN:

162984

Hom.:

AF XY:

0.000174

AC XY:

AN XY:

86240

show subpopulations

Gnomad AFR exome

AF:

0.000103

Gnomad AMR exome

AF:

0.000201

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

165

AN:

1406966

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

694430

show subpopulations

Gnomad4 AFR exome

AF:

0.0000920

Gnomad4 AMR exome

AF:

0.000139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000269

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.000118

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

ExAC

AF:

0.0000726

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.677G>T (p.G226V) alteration is located in exon 1 (coding exon 1) of the NFKBIE gene. This alteration results from a G to T substitution at nucleotide position 677, causing the glycine (G) at amino acid position 226 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

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.7

DANN

Benign

0.97

DEOGEN2

Benign

0.0078

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

.;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.070

.;N

REVEL

Benign

0.063

Sift

Benign

0.096

.;T

Sift4G

Benign

0.30

T;T

Polyphen

0.022

.;B

Vest4

0.084

MVP

0.56

MPC

0.96

ClinPred

0.018

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over