6-44265479-G-C

Position:

• chr6-44265479-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000619360.6(NFKBIE):​c.-133C>G variant causes a 5 prime UTR 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. 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 ENST00000619360.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.463

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]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 88 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIE	NM_004556.3	c.-133C>G		5_prime_UTR_variant	1/6	ENST00000619360.6	NP_004547.3
POLR1C	NM_001318876.2	c.946-176411G>C		intron_variant			NP_001305805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIE	ENST00000275015.9	c.285C>G	p.His95Gln	missense_variant	1/6	1		ENSP00000275015.3
NFKBIE	ENST00000619360.6	c.-133C>G		5_prime_UTR_variant	1/6	1	NM_004556.3	ENSP00000480216.1
NFKBIE	ENST00000477930.2	n.-133C>G		non_coding_transcript_exon_variant	1/3	3		ENSP00000454778.2
NFKBIE	ENST00000477930.2	n.-133C>G		5_prime_UTR_variant	1/3	3		ENSP00000454778.2

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

GnomAD3 exomes AF: 0.0314 AC: 3799 AN: 121138 Hom.: 84 AF XY: 0.0342 AC XY: 2293 AN XY: 66990

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 SAS exome AF: 0.0352

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

Gnomad4 AFR exome AF: 0.00592

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.000146

Gnomad4 SAS exome AF: 0.0373

Gnomad4 FIN exome AF: 0.0545

Gnomad4 NFE exome AF: 0.0433

Gnomad4 OTH exome AF: 0.0324

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

Gnomad4 AFR AF: 0.00741

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0337

Gnomad4 FIN AF: 0.0540

Gnomad4 NFE AF: 0.0439

Gnomad4 OTH AF: 0.0326

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 v4.3

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
MutationTaster	Benign	1.0	N
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.031

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

Other links and lift over

dbSNP: rs28362857; hg19: chr6-44233216;