Genetic Variant NFKBIE:p.His95Gln (chr6-44265479-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000275015.9(NFKBIE):c.285C>G(p.His95Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,527,418 control chromosomes in the GnomAD database, including 1,345 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.029 ( 88 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1257 hom. )

Consequence

NFKBIE
ENST00000275015.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.463

Publications

10 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016144514).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (4471/152240) while in subpopulation NFE AF = 0.0439 (2983/67982). AF 95% confidence interval is 0.0426. There are 88 homozygotes in GnomAd4. There are 2212 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 88 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIE	NM_004556.3 link	c.-133C>G		5_prime_UTR_variant	Exon 1 of 6	ENST00000619360.6	NP_004547.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NFKBIE	ENST00000275015.9 link	c.285C>G	p.His95Gln	missense_variant	Exon 1 of 6	1		ENSP00000275015.3
NFKBIE	ENST00000619360.6 link	c.-133C>G		5_prime_UTR_variant	Exon 1 of 6	1	NM_004556.3	ENSP00000480216.1
NFKBIE	ENST00000477930.2 link	n.-133C>G		non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000454778.2
NFKBIE	ENST00000477930.2 link	n.-133C>G		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000454778.2

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

4472

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00743

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0333

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0314

AC:

3799

AN:

121138

AF XY:

0.0342

show subpopulations

Gnomad AFR exome

AF:

0.00470

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.0552

Gnomad NFE exome

AF:

0.0422

Gnomad OTH exome

AF:

0.0271

GnomAD4 exome

AF:

0.0399

AC:

54851

AN:

1375178

Hom.:

1257

Cov.:

AF XY:

0.0402

AC XY:

27279

AN XY:

678164

show subpopulations

African (AFR)

AF:

0.00592

AC:

173

AN:

29208

American (AMR)

AF:

0.0203

AC:

686

AN:

33758

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

277

AN:

24250

East Asian (EAS)

AF:

0.000146

AC:

AN:

34186

South Asian (SAS)

AF:

0.0373

AC:

2888

AN:

77494

European-Finnish (FIN)

AF:

0.0545

AC:

2284

AN:

41938

Middle Eastern (MID)

AF:

0.0507

AC:

223

AN:

4396

European-Non Finnish (NFE)

AF:

0.0433

AC:

46463

AN:

1072874

Other (OTH)

AF:

0.0324

AC:

1852

AN:

57074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

3381

6762

10144

13525

16906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1772

3544

5316

7088

8860

<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:

0.0294

AC:

4471

AN:

152240

Hom.:

Cov.:

AF XY:

0.0297

AC XY:

2212

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00741

AC:

308

AN:

41558

American (AMR)

AF:

0.0212

AC:

325

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.000581

AC:

AN:

5166

South Asian (SAS)

AF:

0.0337

AC:

163

AN:

4832

European-Finnish (FIN)

AF:

0.0540

AC:

573

AN:

10614

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0439

AC:

2983

AN:

67982

Other (OTH)

AF:

0.0326

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

229

458

688

917

1146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0330

Hom.:

Bravo

AF:

0.0261

TwinsUK

AF:

0.0367

AC:

136

ALSPAC

AF:

0.0436

AC:

168

ESP6500AA

AF:

0.00435

AC:

ESP6500EA

AF:

0.0264

AC:

164

ExAC

AF:

0.0142

AC:

1262

Asia WGS

AF:

0.0130

AC:

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.074

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.46

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.28

REVEL

Benign

0.13

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.028

Vest4

0.049

ClinPred

0.038

GERP RS

1.5

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.031

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over