rs230531

Variant names:

• chr4-102529220-G-A
• rs230531
• NM_003998.4:c.40-616G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-102529220-G-A
• chr4-102529220-G-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.40-616G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 152,000 control chromosomes in the GnomAD database, including 38,489 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 0.70 (38489 hom., cov: 31)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• Publications: 21 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.40-616G>A		intron_variant	Intron 2 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.40-616G>A		intron_variant	Intron 2 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.40-616G>A		intron_variant	Intron 2 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106929 AN: 151882 Hom.: 38454 Cov.: 31

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.702

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.698

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

GnomAD4 genome AF: 0.704 AC: 107004 AN: 152000 Hom.: 38489 Cov.: 31 AF XY: 0.699 AC XY: 51918 AN XY: 74270

African (AFR) AF: 0.842 AC: 34913 AN: 41478

American (AMR) AF: 0.580 AC: 8843 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2370 AN: 3466

East Asian (EAS) AF: 0.575 AC: 2969 AN: 5164

South Asian (SAS) AF: 0.733 AC: 3531 AN: 4816

European-Finnish (FIN) AF: 0.630 AC: 6653 AN: 10562

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45385 AN: 67964

Other (OTH) AF: 0.702 AC: 1479 AN: 2108

Alfa AF: 0.681 Hom.: 9450

Bravo AF: 0.702

Asia WGS AF: 0.642 AC: 2238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.65
DANN	Benign	0.26
PhyloP100		-0.27
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: rs230531; hg19: chr4-103450377;