4-102545592-T-C

Variant names:

• chr4-102545592-T-C
• rs230519
• NM_003998.4:c.258+7636T>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.258+7636T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 151,948 control chromosomes in the GnomAD database, including 38,230 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 0.70 (38230 hom., cov: 31)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.895
• Publications: 22 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 (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.258+7636T>C		intron_variant	Intron 5 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.258+7636T>C		intron_variant	Intron 5 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.255+7636T>C		intron_variant	Intron 5 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106616 AN: 151830 Hom.: 38192 Cov.: 31

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.698

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

GnomAD4 genome AF: 0.702 AC: 106693 AN: 151948 Hom.: 38230 Cov.: 31 AF XY: 0.697 AC XY: 51766 AN XY: 74240

African (AFR) AF: 0.834 AC: 34589 AN: 41496

American (AMR) AF: 0.581 AC: 8855 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2373 AN: 3468

East Asian (EAS) AF: 0.576 AC: 2957 AN: 5136

South Asian (SAS) AF: 0.735 AC: 3536 AN: 4810

European-Finnish (FIN) AF: 0.628 AC: 6635 AN: 10558

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45405 AN: 67918

Other (OTH) AF: 0.701 AC: 1480 AN: 2110

Alfa AF: 0.627 Hom.: 4307

Bravo AF: 0.701

Asia WGS AF: 0.643 AC: 2240 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	1.0
DANN	Benign	0.48
PhyloP100		-0.90
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: rs230519; hg19: chr4-103466749;