4-102583148-C-T

Variant names:

• chr4-102583148-C-T
• rs1005819
• NM_003998.4:c.927+191C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003998.4(NFKB1):​c.927+191C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 151,722 control chromosomes in the GnomAD database, including 13,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.41 (13044 hom., cov: 30)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32
• Publications: 19 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant 4-102583148-C-T is Benign according to our data. Variant chr4-102583148-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.927+191C>T		intron_variant	Intron 10 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.927+191C>T		intron_variant	Intron 10 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.924+191C>T		intron_variant	Intron 10 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62401 AN: 151606 Hom.: 13008 Cov.: 30

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.393

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.412 AC: 62482 AN: 151722 Hom.: 13044 Cov.: 30 AF XY: 0.415 AC XY: 30752 AN XY: 74132

African (AFR) AF: 0.398 AC: 16476 AN: 41358

American (AMR) AF: 0.484 AC: 7376 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1182 AN: 3466

East Asian (EAS) AF: 0.476 AC: 2453 AN: 5150

South Asian (SAS) AF: 0.322 AC: 1543 AN: 4788

European-Finnish (FIN) AF: 0.455 AC: 4788 AN: 10518

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27422 AN: 67892

Other (OTH) AF: 0.389 AC: 818 AN: 2104

Alfa AF: 0.298 Hom.: 785

Bravo AF: 0.416

Asia WGS AF: 0.427 AC: 1482 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-1.1
CADD	Benign	0.50
DANN	Benign	0.32
PhyloP100		-1.3
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: rs1005819; hg19: chr4-103504305;