NM_003998.4:c.2593-22C>G

Variant names:

• chr4-102613403-C-G
• rs3817685
• NM_003998.4:c.2593-22C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003998.4(NFKB1):​c.2593-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,608,992 control chromosomes in the GnomAD database, including 86,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.30 (7489 hom., cov: 31)
  • Exomes 𝑓: 0.33 (79341 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.35
• Publications: 20 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

ENSG00000304360 (HGNC:58861):

LOC105377347 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-102613403-C-G is Benign according to our data. Variant chr4-102613403-C-G is described in ClinVar as Benign. ClinVar VariationId is 1228617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.2593-22C>G		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.2593-22C>G		intron	N/A	NP_001369554.1
	NFKB1	NM_001382626.1		c.2593-22C>G		intron	N/A	NP_001369555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.2593-22C>G		intron	N/A	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.2590-22C>G		intron	N/A	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.2590-22C>G		intron	N/A	ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46097 AN: 151870 Hom.: 7467 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.341 AC: 85186 AN: 249466 AF XY: 0.332

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.357

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.326 AC: 474286 AN: 1457004 Hom.: 79341 Cov.: 33 AF XY: 0.323 AC XY: 233783 AN XY: 724382

African (AFR) AF: 0.211 AC: 7040 AN: 33370

American (AMR) AF: 0.517 AC: 23050 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7735 AN: 26034

East Asian (EAS) AF: 0.372 AC: 14731 AN: 39594

South Asian (SAS) AF: 0.267 AC: 23013 AN: 86058

European-Finnish (FIN) AF: 0.347 AC: 18525 AN: 53342

Middle Eastern (MID) AF: 0.267 AC: 1438 AN: 5392

European-Non Finnish (NFE) AF: 0.324 AC: 359184 AN: 1108488

Other (OTH) AF: 0.325 AC: 19570 AN: 60146

GnomAD4 genome AF: 0.304 AC: 46141 AN: 151988 Hom.: 7489 Cov.: 31 AF XY: 0.308 AC XY: 22892 AN XY: 74276

African (AFR) AF: 0.224 AC: 9281 AN: 41464

American (AMR) AF: 0.408 AC: 6240 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1017 AN: 3472

East Asian (EAS) AF: 0.412 AC: 2123 AN: 5158

South Asian (SAS) AF: 0.273 AC: 1313 AN: 4814

European-Finnish (FIN) AF: 0.357 AC: 3774 AN: 10560

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21482 AN: 67924

Other (OTH) AF: 0.280 AC: 590 AN: 2108

Alfa AF: 0.237 Hom.: 819

Bravo AF: 0.305

Asia WGS AF: 0.362 AC: 1256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied by a panel of primary immunodeficiencies. Number of patients: 62. Only high quality variants are reported.

Immunodeficiency, common variable, 12 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.096
DANN	Benign	0.54
PhyloP100		-1.4
BranchPoint Hunter		1.0
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: rs3817685; hg19: chr4-103534560; COSMIC: COSV56956817;