rs4648068

Positions:

• chr4-102597148-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003998.4(NFKB1):​c.1496-372A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 152,036 control chromosomes in the GnomAD database, including 7,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7760 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.46

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 4-102597148-A-G is Benign according to our data. Variant chr4-102597148-A-G is described in ClinVar as [Benign]. Clinvar id is 1244688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.1496-372A>G		intron_variant		ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.1496-372A>G		intron_variant		1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.1493-372A>G		intron_variant		1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47326 AN: 151918 Hom.: 7744 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.312 AC: 47362 AN: 152036 Hom.: 7760 Cov.: 32 AF XY: 0.316 AC XY: 23499 AN XY: 74328

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.292

Alfa AF: 0.339 Hom.: 3221

Bravo AF: 0.315

Asia WGS AF: 0.367 AC: 1274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

This variant is associated with the following publications: (PMID: 26345753, 25888547) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.059
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs4648068; hg19: chr4-103518305;