chr4-102525666-AT-A

Variant names:

• chr4-102525666-AT-A
• rs41477752
• NM_003998.4:c.39+118delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003998.4(NFKB1):​c.39+118delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 979,340 control chromosomes in the GnomAD database, including 2,098 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.091 (993 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1105 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 1 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: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 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.39+118delT		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.39+118delT		intron	N/A	NP_001369554.1	P19838-2
	NFKB1	NM_001382626.1		c.39+118delT		intron	N/A	NP_001369555.1	P19838-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.39+110delT		intron	N/A	ENSP00000226574.4	P19838-2
	NFKB1	ENST00000394820.8	TSL:1	c.39+110delT		intron	N/A	ENSP00000378297.4	P19838-1
	NFKB1	ENST00000505458.5	TSL:1	c.39+110delT		intron	N/A	ENSP00000424790.1	P19838-1

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 13773 AN: 151786 Hom.: 986 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.0509

Gnomad SAS AF: 0.0347

Gnomad FIN AF: 0.0656

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0768

GnomAD4 exome AF: 0.0415 AC: 34369 AN: 827436 Hom.: 1105 AF XY: 0.0410 AC XY: 17358 AN XY: 423702

African (AFR) AF: 0.196 AC: 3497 AN: 17846

American (AMR) AF: 0.0323 AC: 695 AN: 21490

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 266 AN: 18320

East Asian (EAS) AF: 0.0505 AC: 1615 AN: 31996

South Asian (SAS) AF: 0.0270 AC: 1488 AN: 55086

European-Finnish (FIN) AF: 0.0614 AC: 2820 AN: 45956

Middle Eastern (MID) AF: 0.0408 AC: 118 AN: 2892

European-Non Finnish (NFE) AF: 0.0368 AC: 21954 AN: 595828

Other (OTH) AF: 0.0504 AC: 1916 AN: 38022

GnomAD4 genome AF: 0.0909 AC: 13804 AN: 151904 Hom.: 993 Cov.: 31 AF XY: 0.0893 AC XY: 6625 AN XY: 74224

African (AFR) AF: 0.205 AC: 8477 AN: 41416

American (AMR) AF: 0.0488 AC: 743 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3472

East Asian (EAS) AF: 0.0505 AC: 261 AN: 5172

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4812

European-Finnish (FIN) AF: 0.0656 AC: 690 AN: 10526

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3166 AN: 67956

Other (OTH) AF: 0.0760 AC: 160 AN: 2106

Alfa AF: 0.0152 Hom.: 2

Bravo AF: 0.0953

Asia WGS AF: 0.0570 AC: 198 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
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: rs41477752; hg19: chr4-103446823;