rs72696119

Positions:

• chr4-102501347-C-G
• chr4-102501347-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000394820.8(NFKB1):​c.-449C>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 0.429 in 151,462 control chromosomes in the GnomAD database, including 14,261 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 0.43 (14245 hom., cov: 33)
  • Exomes 𝑓: 0.41 (16 hom.)
• Consequence: NFKB1 ENST00000394820.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.953

Genes affected

NFKB1 (HGNC:7794): (nuclear factor kappa B subunit 1) This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappa-B (NFKB) protein complex. NFKB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth. NFKB is a critical regulator of the immediate-early response to viral infection. Alternative splicing results in multiple transcript variants encoding different isoforms, at least one of which is proteolytically processed. [provided by RefSeq, Aug 2020]

LOC105377621 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC105377621	NR_136202.1	n.48+1092G>C		intron_variant, non_coding_transcript_variant
NFKB1	NM_003998.4			upstream_gene_variant		ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000394820.8	c.-449C>G		5_prime_UTR_variant	1/24	1		ENSP00000378297	A2
NFKB1	ENST00000507079.6	c.-495C>G		5_prime_UTR_variant	1/25	5		ENSP00000426147
NFKB1	ENST00000226574.9			upstream_gene_variant		1	NM_003998.4	ENSP00000226574	P4
	ENST00000563833.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.429 AC: 64883 AN: 151160 Hom.: 14219 Cov.: 33

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.403

GnomAD4 exome AF: 0.412 AC: 80 AN: 194 Hom.: 16 Cov.: 0 AF XY: 0.392 AC XY: 51 AN XY: 130

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.300

GnomAD4 genome AF: 0.429 AC: 64950 AN: 151268 Hom.: 14245 Cov.: 33 AF XY: 0.430 AC XY: 31805 AN XY: 73926

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.487

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.399

Alfa AF: 0.289 Hom.: 727

Bravo AF: 0.439

Asia WGS AF: 0.345 AC: 1157 AN: 3358

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.90

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: rs72696119; hg19: chr4-103422504;