NM_003998.4:c.2750-149C>T

Variant names:

• chr4-102616285-C-T
• rs1609798
• NM_003998.4:c.2750-149C>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.2750-149C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 772,700 control chromosomes in the GnomAD database, including 38,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6318 hom., cov: 32)
  • Exomes 𝑓: 0.31 (32024 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 55 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:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-102616285-C-T is Benign according to our data. Variant chr4-102616285-C-T is described in ClinVar as Benign. ClinVar VariationId is 1225916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.2750-149C>T		intron_variant	Intron 23 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.2750-149C>T		intron_variant	Intron 23 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.2747-149C>T		intron_variant	Intron 23 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40387 AN: 151984 Hom.: 6302 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.312 AC: 193834 AN: 620596 Hom.: 32024 AF XY: 0.312 AC XY: 100810 AN XY: 323574

African (AFR) AF: 0.0936 AC: 1532 AN: 16364

American (AMR) AF: 0.485 AC: 13124 AN: 27068

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 4169 AN: 14880

East Asian (EAS) AF: 0.336 AC: 11657 AN: 34660

South Asian (SAS) AF: 0.289 AC: 14341 AN: 49620

European-Finnish (FIN) AF: 0.351 AC: 13095 AN: 37256

Middle Eastern (MID) AF: 0.244 AC: 543 AN: 2226

European-Non Finnish (NFE) AF: 0.309 AC: 125629 AN: 406942

Other (OTH) AF: 0.309 AC: 9744 AN: 31580

GnomAD4 genome AF: 0.266 AC: 40408 AN: 152104 Hom.: 6318 Cov.: 32 AF XY: 0.270 AC XY: 20100 AN XY: 74356

African (AFR) AF: 0.105 AC: 4367 AN: 41526

American (AMR) AF: 0.371 AC: 5670 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 944 AN: 3472

East Asian (EAS) AF: 0.386 AC: 1997 AN: 5168

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3827 AN: 10554

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21276 AN: 67958

Other (OTH) AF: 0.256 AC: 542 AN: 2116

Alfa AF: 0.299 Hom.: 12165

Bravo AF: 0.262

Asia WGS AF: 0.356 AC: 1235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.71
DANN	Benign	0.63
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1609798; hg19: chr4-103537442; COSMIC: COSV56957073;