NM_003998.4:c.2592+58T>A

Variant names:

• chr4-102612664-T-A
• rs4648110
• NM_003998.4:c.2592+58T>A

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.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:3
• Conservation: PhyloP100: -0.582
• Publications: 45 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=-0.9).
• BP6: Variant 4-102612664-T-A is Benign according to our data. Variant chr4-102612664-T-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.2592+58T>A		intron_variant	Intron 22 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.2592+58T>A		intron_variant	Intron 22 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.2589+58T>A		intron_variant	Intron 22 of 23	1		ENSP00000424790.1

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

African (AFR) AF: 0.310 AC: 9348 AN: 30138

American (AMR) AF: 0.110 AC: 4647 AN: 42342

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 4997 AN: 24122

East Asian (EAS) AF: 0.0689 AC: 2670 AN: 38736

South Asian (SAS) AF: 0.221 AC: 17812 AN: 80598

European-Finnish (FIN) AF: 0.132 AC: 6500 AN: 49328

Middle Eastern (MID) AF: 0.254 AC: 1009 AN: 3976

European-Non Finnish (NFE) AF: 0.204 AC: 201829 AN: 991752

Other (OTH) AF: 0.200 AC: 11040 AN: 55204

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

African (AFR) AF: 0.303 AC: 12567 AN: 41454

American (AMR) AF: 0.158 AC: 2410 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 771 AN: 3472

East Asian (EAS) AF: 0.0604 AC: 313 AN: 5180

South Asian (SAS) AF: 0.205 AC: 989 AN: 4820

European-Finnish (FIN) AF: 0.115 AC: 1212 AN: 10578

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13848 AN: 67980

Other (OTH) AF: 0.232 AC: 489 AN: 2110

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:3

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

- -

Jun 19, 2021

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 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		-0.58
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: rs4648110; hg19: chr4-103533821; COSMIC: COSV56961257;