Genetic Variant ENST00000275015.9:c.365G>A (chr6-44265399-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000275015.9(NFKBIE):c.365G>A(p.Ser122Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000742 in 1,549,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S122R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

NFKBIE
ENST00000275015.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.318

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005528748).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000275015.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIE	NM_004556.3	MANE Select	c.-53G>A		5_prime_UTR	Exon 1 of 6	NP_004547.3	Q7LC14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFKBIE	ENST00000275015.9	TSL:1	c.365G>A	p.Ser122Asn	missense	Exon 1 of 6	ENSP00000275015.3	O00221
NFKBIE	ENST00000619360.6	TSL:1 MANE Select	c.-53G>A		5_prime_UTR	Exon 1 of 6	ENSP00000480216.1	Q7LC14
NFKBIE	ENST00000890578.1		c.-53G>A		5_prime_UTR	Exon 1 of 6	ENSP00000560637.1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000938

AC:

AN:

149286

AF XY:

0.0000482

show subpopulations

Gnomad AFR exome

AF:

0.00227

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1397622

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

AN XY:

691514

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

30888

American (AMR)

AF:

0.0000519

AC:

AN:

38522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25008

East Asian (EAS)

AF:

0.00

AC:

AN:

35708

South Asian (SAS)

AF:

0.00

AC:

AN:

79884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4270

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1087370

Other (OTH)

AF:

0.0000862

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000361

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.00103

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000656

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.19

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.25

M_CAP

Benign

0.023

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.32

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.070

REVEL

Benign

0.018

Sift

Uncertain

0.0050

Sift4G

Benign

0.14

Polyphen

0.20

Vest4

0.055

MVP

0.35

MPC

0.73

ClinPred

0.055

GERP RS

2.8

PromoterAI

0.20

Neutral

(source)

Varity_R

0.073

gMVP

0.036

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over