rs4648110

chr4-102612664-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003998.4(NFKB1):c.2592+58T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,468,294 control chromosomes in the GnomAD database, including 31,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3979 hom., cov: 32)
  • Exomes 𝑓: 0.20 (27328 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.582

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]

LOC105377347 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-102612664-T-A is Benign according to our data. Variant chr4-102612664-T-A is described in ClinVar as [Benign]. Clinvar id is 1256826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4	c.2592+58T>A		intron_variant		ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.2592+58T>A		intron_variant		1	NM_003998.4	P4

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32923 AN: 151980 Hom.: 3980 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0603

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.197 AC: 259852 AN: 1316196 Hom.: 27328 AF XY: 0.199 AC XY: 130971 AN XY: 658598

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.0689

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.204

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.216 AC: 32923 AN: 152098 Hom.: 3979 Cov.: 32 AF XY: 0.211 AC XY: 15711 AN XY: 74346

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0604

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.232

Alfa AF: 0.210 Hom.: 427

Bravo AF: 0.220

Asia WGS AF: 0.132 AC: 458 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.8
Dann	Benign	0.65

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: rs4648110; hg19: chr4-103533821; COSMIC: COSV56961257;