4-102536261-T-C

Variant names:

• chr4-102536261-T-C
• rs230529
• NM_003998.4:c.160-1597T>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.160-1597T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 151,890 control chromosomes in the GnomAD database, including 26,389 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 0.59 (26389 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0230
• Publications: 34 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.160-1597T>C		intron_variant	Intron 4 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.160-1597T>C		intron_variant	Intron 4 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.157-1597T>C		intron_variant	Intron 4 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89184 AN: 151772 Hom.: 26378 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.607

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

GnomAD4 genome AF: 0.587 AC: 89218 AN: 151890 Hom.: 26389 Cov.: 32 AF XY: 0.585 AC XY: 43415 AN XY: 74240

African (AFR) AF: 0.584 AC: 24144 AN: 41372

American (AMR) AF: 0.519 AC: 7918 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2295 AN: 3472

East Asian (EAS) AF: 0.525 AC: 2713 AN: 5168

South Asian (SAS) AF: 0.693 AC: 3342 AN: 4820

European-Finnish (FIN) AF: 0.547 AC: 5765 AN: 10544

Middle Eastern (MID) AF: 0.712 AC: 208 AN: 292

European-Non Finnish (NFE) AF: 0.603 AC: 40968 AN: 67956

Other (OTH) AF: 0.611 AC: 1289 AN: 2108

Alfa AF: 0.599 Hom.: 48841

Bravo AF: 0.581

Asia WGS AF: 0.582 AC: 2024 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.57
PhyloP100		0.023
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: rs230529; hg19: chr4-103457418;