4-102613400-C-T

Variant names:

• chr4-102613400-C-T
• rs4648117
• NM_003998.4:c.2593-25C>T

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.2593-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,609,468 control chromosomes in the GnomAD database, including 1,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (128 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1357 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730
• Publications: 8 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: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-102613400-C-T is Benign according to our data. Variant chr4-102613400-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0563 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.2593-25C>T		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.2593-25C>T		intron	N/A	NP_001369554.1
	NFKB1	NM_001382626.1		c.2593-25C>T		intron	N/A	NP_001369555.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.2593-25C>T		intron	N/A	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.2590-25C>T		intron	N/A	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.2590-25C>T		intron	N/A	ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5889 AN: 152114 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0623

Gnomad SAS AF: 0.0341

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0405 AC: 10091 AN: 249444 AF XY: 0.0407

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0769

Gnomad FIN exome AF: 0.0616

Gnomad NFE exome AF: 0.0461

Gnomad OTH exome AF: 0.0374

GnomAD4 exome AF: 0.0423 AC: 61694 AN: 1457236 Hom.: 1357 Cov.: 29 AF XY: 0.0421 AC XY: 30520 AN XY: 724288

African (AFR) AF: 0.0216 AC: 720 AN: 33374

American (AMR) AF: 0.0170 AC: 758 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 296 AN: 25984

East Asian (EAS) AF: 0.0585 AC: 2317 AN: 39590

South Asian (SAS) AF: 0.0286 AC: 2461 AN: 86016

European-Finnish (FIN) AF: 0.0619 AC: 3301 AN: 53332

Middle Eastern (MID) AF: 0.0195 AC: 104 AN: 5338

European-Non Finnish (NFE) AF: 0.0445 AC: 49317 AN: 1108888

Other (OTH) AF: 0.0402 AC: 2420 AN: 60130

GnomAD4 genome AF: 0.0387 AC: 5896 AN: 152232 Hom.: 128 Cov.: 32 AF XY: 0.0393 AC XY: 2924 AN XY: 74432

African (AFR) AF: 0.0251 AC: 1042 AN: 41544

American (AMR) AF: 0.0282 AC: 432 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.0619 AC: 320 AN: 5170

South Asian (SAS) AF: 0.0347 AC: 167 AN: 4812

European-Finnish (FIN) AF: 0.0657 AC: 697 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3063 AN: 68006

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.0367 Hom.: 17

Bravo AF: 0.0359

Asia WGS AF: 0.0480 AC: 165 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.44
PhyloP100		0.073
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: rs4648117; hg19: chr4-103534557;