4-102615513-A-G

Variant names:

• chr4-102615513-A-G
• rs4648135
• NM_003998.4:c.2750-921A>G

Variant summary

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

The NM_003998.4(NFKB1):​c.2750-921A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 152,320 control chromosomes in the GnomAD database, including 689 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 0.083 (689 hom., cov: 33)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 26 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

ENSG00000304360 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.2750-921A>G		intron_variant	Intron 23 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.2750-921A>G		intron_variant	Intron 23 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.2747-921A>G		intron_variant	Intron 23 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 12589 AN: 152202 Hom.: 689 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0534

Gnomad OTH AF: 0.0611

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

GnomAD4 genome AF: 0.0828 AC: 12615 AN: 152320 Hom.: 689 Cov.: 33 AF XY: 0.0817 AC XY: 6089 AN XY: 74492

African (AFR) AF: 0.161 AC: 6704 AN: 41550

American (AMR) AF: 0.0441 AC: 675 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.0636 AC: 330 AN: 5186

South Asian (SAS) AF: 0.0371 AC: 179 AN: 4830

European-Finnish (FIN) AF: 0.0781 AC: 830 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0534 AC: 3634 AN: 68026

Other (OTH) AF: 0.0605 AC: 128 AN: 2116

Alfa AF: 0.0537 Hom.: 493

Bravo AF: 0.0843

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.034
DANN	Benign	0.24
PhyloP100		-2.2
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: rs4648135; hg19: chr4-103536670;