6-44265479-G-C

Variant names:

• chr6-44265479-G-C
• rs28362857
• ENST00000275015.9:c.285C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.463
• Publications: 10 publications found

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]

ACMG classification

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

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.-133C>G		5_prime_UTR	Exon 1 of 6	NP_004547.3	Q7LC14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIE	ENST00000275015.9	TSL:1	c.285C>G	p.His95Gln	missense	Exon 1 of 6	ENSP00000275015.3	O00221
	NFKBIE	ENST00000619360.6	TSL:1 MANE Select	c.-133C>G		5_prime_UTR	Exon 1 of 6	ENSP00000480216.1	Q7LC14
	NFKBIE	ENST00000890578.1		c.-133C>G		5_prime_UTR	Exon 1 of 6	ENSP00000560637.1

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4472 AN: 152132 Hom.: 88 Cov.: 33

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

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.: 33 AF XY: 0.0402 AC XY: 27279 AN XY: 678164

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: 5 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

GnomAD4 genome AF: 0.0294 AC: 4471 AN: 152240 Hom.: 88 Cov.: 33 AF XY: 0.0297 AC XY: 2212 AN XY: 74436

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: 31 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 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: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0439 AC: 2983 AN: 67982

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0330 Hom.: 28

Bravo AF: 0.0261

TwinsUK AF: 0.0367 AC: 136

ALSPAC AF: 0.0436 AC: 168

ESP6500AA AF: 0.00435 AC: 13

ESP6500EA AF: 0.0264 AC: 164

ExAC AF: 0.0142 AC: 1262

Asia WGS AF: 0.0130 AC: 44 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.46
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.028	D
Polyphen		0.0010	B
Vest4		0.049
MutPred		0.076		Gain of MoRF binding (P = 0.0913)
MPC		0.77
ClinPred		0.038	T
GERP RS		1.5
PromoterAI		0.011	Neutral
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)

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

Other links and lift over

dbSNP: rs28362857; hg19: chr6-44233216;