rs230541

Variant names:

• chr4-102576628-G-A
• rs230541
• NM_003998.4:c.408-248G>A

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.408-248G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 151,932 control chromosomes in the GnomAD database, including 25,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.58 (25981 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.394
• Publications: 18 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: STRONG, MODERATE 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=-0.91).
• BP6: Variant 4-102576628-G-A is Benign according to our data. Variant chr4-102576628-G-A is described in ClinVar as Benign. ClinVar VariationId is 1225045.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.654 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.408-248G>A		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.408-248G>A		intron	N/A	NP_001369554.1	P19838-2
	NFKB1	NM_001382626.1		c.408-248G>A		intron	N/A	NP_001369555.1	P19838-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.408-248G>A		intron	N/A	ENSP00000226574.4	P19838-2
	NFKB1	ENST00000394820.8	TSL:1	c.405-248G>A		intron	N/A	ENSP00000378297.4	P19838-1
	NFKB1	ENST00000505458.5	TSL:1	c.405-248G>A		intron	N/A	ENSP00000424790.1	P19838-1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88526 AN: 151814 Hom.: 25966 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.583 AC: 88564 AN: 151932 Hom.: 25981 Cov.: 32 AF XY: 0.580 AC XY: 43067 AN XY: 74250

African (AFR) AF: 0.585 AC: 24230 AN: 41410

American (AMR) AF: 0.514 AC: 7850 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2282 AN: 3466

East Asian (EAS) AF: 0.522 AC: 2692 AN: 5160

South Asian (SAS) AF: 0.674 AC: 3243 AN: 4814

European-Finnish (FIN) AF: 0.545 AC: 5749 AN: 10552

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40461 AN: 67962

Other (OTH) AF: 0.606 AC: 1276 AN: 2104

Alfa AF: 0.586 Hom.: 5451

Bravo AF: 0.578

Asia WGS AF: 0.572 AC: 1993 AN: 3478

ClinVar

ClinVar submissions

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	-0.91
CADD	Benign	0.75
DANN	Benign	0.65
PhyloP100		-0.39
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: rs230541; hg19: chr4-103497785;