4-102579718-T-C

Variant names:

• chr4-102579718-T-C
• rs230544
• NM_003998.4:c.730+679T>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.730+679T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 149,370 control chromosomes in the GnomAD database, including 26,008 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 0.59 (26008 hom., cov: 27)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.626
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.730+679T>C		intron_variant	Intron 8 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.730+679T>C		intron_variant	Intron 8 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.727+679T>C		intron_variant	Intron 8 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 87727 AN: 149306 Hom.: 26004 Cov.: 27

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.604

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

GnomAD4 genome AF: 0.587 AC: 87732 AN: 149370 Hom.: 26008 Cov.: 27 AF XY: 0.584 AC XY: 42509 AN XY: 72772

African (AFR) AF: 0.600 AC: 24488 AN: 40780

American (AMR) AF: 0.515 AC: 7714 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2284 AN: 3466

East Asian (EAS) AF: 0.523 AC: 2676 AN: 5114

South Asian (SAS) AF: 0.678 AC: 3228 AN: 4762

European-Finnish (FIN) AF: 0.539 AC: 5085 AN: 9442

Middle Eastern (MID) AF: 0.710 AC: 203 AN: 286

European-Non Finnish (NFE) AF: 0.595 AC: 40229 AN: 67566

Other (OTH) AF: 0.607 AC: 1256 AN: 2068

Alfa AF: 0.577 Hom.: 3145

Bravo AF: 0.583

Asia WGS AF: 0.571 AC: 1984 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.80
PhyloP100		-0.63
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: rs230544; hg19: chr4-103500875;