chr4-102567334-G-A

Variant names:

• chr4-102567334-G-A
• rs230496
• NM_003998.4:c.407+199G>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.407+199G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 151,864 control chromosomes in the GnomAD database, including 26,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.59 (26839 hom., cov: 31)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.496
• 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-102567334-G-A is Benign according to our data. Variant chr4-102567334-G-A is described in ClinVar as Benign. ClinVar VariationId is 1244754.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.407+199G>A		intron_variant	Intron 6 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.407+199G>A		intron_variant	Intron 6 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.404+199G>A		intron_variant	Intron 6 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89934 AN: 151748 Hom.: 26824 Cov.: 31

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.610

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

GnomAD4 genome AF: 0.592 AC: 89974 AN: 151864 Hom.: 26839 Cov.: 31 AF XY: 0.590 AC XY: 43728 AN XY: 74178

African (AFR) AF: 0.601 AC: 24888 AN: 41412

American (AMR) AF: 0.518 AC: 7904 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2291 AN: 3468

East Asian (EAS) AF: 0.526 AC: 2717 AN: 5164

South Asian (SAS) AF: 0.679 AC: 3275 AN: 4820

European-Finnish (FIN) AF: 0.548 AC: 5750 AN: 10488

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

European-Non Finnish (NFE) AF: 0.604 AC: 41074 AN: 67954

Other (OTH) AF: 0.615 AC: 1291 AN: 2100

Alfa AF: 0.591 Hom.: 3308

Bravo AF: 0.587

Asia WGS AF: 0.579 AC: 2015 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.59
PhyloP100		-0.50
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: rs230496; hg19: chr4-103488491;