rs4648069

chr4-102597322-C-A

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.1496-198C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 152,266 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.041 (241 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.218

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=-0.85).
• BP6: Variant 4-102597322-C-A is Benign according to our data. Variant chr4-102597322-C-A is described in ClinVar as [Benign]. Clinvar id is 1270378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4	c.1496-198C>A		intron_variant		ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.1496-198C>A		intron_variant		1	NM_003998.4	P4

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6169 AN: 152148 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0277

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

GnomAD4 genome AF: 0.0406 AC: 6177 AN: 152266 Hom.: 241 Cov.: 32 AF XY: 0.0388 AC XY: 2889 AN XY: 74450

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0358 Hom.: 15

Bravo AF: 0.0428

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

Jun 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.92
Dann	Benign	0.56

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: rs4648069; hg19: chr4-103518479;