rs4647992

Variant names:

• chr4-102534190-C-T
• rs4647992
• NM_003998.4:c.159+305C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003998.4(NFKB1):​c.159+305C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 152,218 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.058 (283 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.126
• Publications: 20 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-102534190-C-T is Benign according to our data. Variant chr4-102534190-C-T is described in ClinVar as Benign. ClinVar VariationId is 1274917.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.159+305C>T		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.159+305C>T		intron	N/A	NP_001369554.1
	NFKB1	NM_001382626.1		c.159+305C>T		intron	N/A	NP_001369555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.159+305C>T		intron	N/A	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.156+305C>T		intron	N/A	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.156+305C>T		intron	N/A	ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.0578 AC: 8788 AN: 152100 Hom.: 283 Cov.: 32

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0492

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

GnomAD4 genome AF: 0.0578 AC: 8802 AN: 152218 Hom.: 283 Cov.: 32 AF XY: 0.0576 AC XY: 4289 AN XY: 74416

African (AFR) AF: 0.0928 AC: 3854 AN: 41538

American (AMR) AF: 0.0354 AC: 541 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.0496 AC: 257 AN: 5184

South Asian (SAS) AF: 0.0347 AC: 167 AN: 4816

European-Finnish (FIN) AF: 0.0652 AC: 692 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0452 AC: 3075 AN: 68010

Other (OTH) AF: 0.0487 AC: 103 AN: 2114

Alfa AF: 0.0478 Hom.: 797

Bravo AF: 0.0584

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.73
PhyloP100		0.13
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: rs4647992; hg19: chr4-103455347;