chr4-102604351-G-C

Variant names:

• chr4-102604351-G-C
• rs12509517
• NM_003998.4:c.1753-2145G>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.1753-2145G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 151,900 control chromosomes in the GnomAD database, including 5,875 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 0.25 (5875 hom., cov: 31)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 14 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

LOC105377347 (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 (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.1753-2145G>C		intron_variant	Intron 16 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.1753-2145G>C		intron_variant	Intron 16 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.1750-2145G>C		intron_variant	Intron 16 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37792 AN: 151782 Hom.: 5860 Cov.: 31

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.249 AC: 37801 AN: 151900 Hom.: 5875 Cov.: 31 AF XY: 0.255 AC XY: 18946 AN XY: 74204

African (AFR) AF: 0.0722 AC: 2996 AN: 41498

American (AMR) AF: 0.381 AC: 5811 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 976 AN: 3466

East Asian (EAS) AF: 0.414 AC: 2134 AN: 5152

South Asian (SAS) AF: 0.269 AC: 1295 AN: 4818

European-Finnish (FIN) AF: 0.343 AC: 3606 AN: 10504

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20151 AN: 67912

Other (OTH) AF: 0.247 AC: 517 AN: 2096

Alfa AF: 0.161 Hom.: 351

Bravo AF: 0.246

Asia WGS AF: 0.348 AC: 1206 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	15
DANN	Benign	0.73
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs12509517; hg19: chr4-103525508; COSMIC: COSV56957344;