rs4648004

Variant names:

• chr4-102539950-A-G
• rs4648004
• NM_003998.4:c.258+1994A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003998.4(NFKB1):​c.258+1994A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,040 control chromosomes in the GnomAD database, including 6,260 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 0.26 (6260 hom., cov: 31)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.258+1994A>G		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+1994A>G		intron_variant	Intron 5 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.255+1994A>G		intron_variant	Intron 5 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39069 AN: 151922 Hom.: 6257 Cov.: 31

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.257 AC: 39074 AN: 152040 Hom.: 6260 Cov.: 31 AF XY: 0.258 AC XY: 19185 AN XY: 74284

Gnomad4 AFR AF: 0.0717

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.342

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.276

Alfa AF: 0.311 Hom.: 1597

Bravo AF: 0.241

Asia WGS AF: 0.174 AC: 605 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.018
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs4648004; hg19: chr4-103461107;