rs1598859

Variant names:

• chr4-102585287-T-C
• rs1598859
• NM_003998.4:c.1066+467T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003998.4(NFKB1):​c.1066+467T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,096 control chromosomes in the GnomAD database, including 9,174 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 0.34 (9174 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 44 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.1066+467T>C		intron_variant	Intron 11 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.1066+467T>C		intron_variant	Intron 11 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.1063+467T>C		intron_variant	Intron 11 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51538 AN: 151978 Hom.: 9158 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.339

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.339 AC: 51571 AN: 152096 Hom.: 9174 Cov.: 32 AF XY: 0.342 AC XY: 25462 AN XY: 74354

African (AFR) AF: 0.253 AC: 10497 AN: 41490

American (AMR) AF: 0.444 AC: 6781 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1136 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2209 AN: 5174

South Asian (SAS) AF: 0.287 AC: 1386 AN: 4830

European-Finnish (FIN) AF: 0.390 AC: 4117 AN: 10554

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24390 AN: 67976

Other (OTH) AF: 0.335 AC: 708 AN: 2114

Alfa AF: 0.349 Hom.: 5485

Bravo AF: 0.342

Asia WGS AF: 0.371 AC: 1289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.6
DANN	Benign	0.56
PhyloP100		0.070
Mutation Taster		=100/0	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: rs1598859; hg19: chr4-103506444;