4-102500997-CATTG-C

Variant names:

• chr4-102500997-CATTG-C
• rs28362491
• ENST00000966659.1:c.-794_-791delATTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000966659.1(NFKB1):​c.-794_-791delATTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 153,546 control chromosomes in the GnomAD database, including 14,272 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14166 hom., cov: 0)
  • Exomes 𝑓: 0.32 (106 hom.)
• Consequence: NFKB1 ENST00000966659.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720
• Publications: 327 publications found

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]

NFKB1 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 12

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260651 (HGNC:):

NFKB1-AS1 (HGNC:58149):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000966659.1. 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
	NFKB1-AS1	NR_136202.1		n.48+1438_48+1441delCAAT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000966659.1		c.-794_-791delATTG		5_prime_UTR	Exon 1 of 24	ENSP00000636718.1
	ENSG00000260651	ENST00000563833.1	TSL:6	n.319_322delCAAT		non_coding_transcript_exon	Exon 1 of 1
	NFKB1-AS1	ENST00000843825.1		n.49+1438_49+1441delCAAT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64938 AN: 151662 Hom.: 14138 Cov.: 0

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.323 AC: 570 AN: 1764 Hom.: 106 AF XY: 0.327 AC XY: 353 AN XY: 1080

African (AFR) AF: 0.350 AC: 7 AN: 20

American (AMR) AF: 0.429 AC: 6 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 5 AN: 36

East Asian (EAS) AF: 0.313 AC: 50 AN: 160

South Asian (SAS) AF: 0.167 AC: 12 AN: 72

European-Finnish (FIN) AF: 0.489 AC: 44 AN: 90

Middle Eastern (MID) AF: 0.167 AC: 2 AN: 12

European-Non Finnish (NFE) AF: 0.331 AC: 421 AN: 1270

Other (OTH) AF: 0.256 AC: 23 AN: 90

GnomAD4 genome AF: 0.428 AC: 65010 AN: 151782 Hom.: 14166 Cov.: 0 AF XY: 0.429 AC XY: 31815 AN XY: 74188

African (AFR) AF: 0.494 AC: 20462 AN: 41388

American (AMR) AF: 0.485 AC: 7412 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1155 AN: 3468

East Asian (EAS) AF: 0.403 AC: 2073 AN: 5150

South Asian (SAS) AF: 0.297 AC: 1435 AN: 4826

European-Finnish (FIN) AF: 0.447 AC: 4714 AN: 10542

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26510 AN: 67844

Other (OTH) AF: 0.398 AC: 836 AN: 2100

Alfa AF: 0.416 Hom.: 1645

Bravo AF: 0.439

Asia WGS AF: 0.354 AC: 1226 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.072

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28362491; hg19: chr4-103422154;