4-102609955-A-G

Variant names:

• chr4-102609955-A-G
• rs3774968
• NM_003998.4:c.2228-620A>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.2228-620A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 152,094 control chromosomes in the GnomAD database, including 31,574 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 0.63 (31574 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.877
• Publications: 22 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 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.2228-620A>G		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.2228-620A>G		intron	N/A	NP_001369554.1
	NFKB1	NM_001382626.1		c.2228-620A>G		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.2228-620A>G		intron	N/A	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.2225-620A>G		intron	N/A	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.2225-620A>G		intron	N/A	ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96328 AN: 151976 Hom.: 31516 Cov.: 32

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.616

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

GnomAD4 genome AF: 0.634 AC: 96434 AN: 152094 Hom.: 31574 Cov.: 32 AF XY: 0.632 AC XY: 46964 AN XY: 74356

African (AFR) AF: 0.806 AC: 33454 AN: 41504

American (AMR) AF: 0.625 AC: 9550 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1852 AN: 3470

East Asian (EAS) AF: 0.537 AC: 2769 AN: 5160

South Asian (SAS) AF: 0.525 AC: 2534 AN: 4828

European-Finnish (FIN) AF: 0.539 AC: 5692 AN: 10560

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38582 AN: 67974

Other (OTH) AF: 0.609 AC: 1283 AN: 2108

Alfa AF: 0.538 Hom.: 3495

Bravo AF: 0.648

Asia WGS AF: 0.564 AC: 1958 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.54
PhyloP100		-0.88
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: rs3774968; hg19: chr4-103531112;