4-102593584-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003998.4(NFKB1):c.1210+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,600,628 control chromosomes in the GnomAD database, including 93,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8295 hom., cov: 32)

Exomes 𝑓: 0.34 ( 85322 hom. )

Consequence

NFKB1
NM_003998.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.957

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 4-102593584-T-C is Benign according to our data. Variant chr4-102593584-T-C is described in ClinVar as [Benign]. Clinvar id is 1168266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102593584-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4 link	c.1210+16T>C		intron_variant	Intron 12 of 23	ENST00000226574.9	NP_003989.2	P19838-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9 link	c.1210+16T>C		intron_variant	Intron 12 of 23	1	NM_003998.4	ENSP00000226574.4		P19838-2
NFKB1	ENST00000505458.5 link	c.1207+16T>C		intron_variant	Intron 12 of 23	1		ENSP00000424790.1		P19838-1

Frequencies

GnomAD3 genomes

AF:

0.323

AC:

49083

AN:

151876

Hom.:

8281

Cov.:

show subpopulations

Gnomad AFR

AF:

0.256

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.414

Gnomad ASJ

AF:

0.303

Gnomad EAS

AF:

0.426

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.384

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.305

GnomAD3 exomes

AF:

0.358

AC:

87122

AN:

243112

Hom.:

16735

AF XY:

0.349

AC XY:

45861

AN XY:

131590

show subpopulations

Gnomad AFR exome

AF:

0.256

Gnomad AMR exome

AF:

0.541

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.443

Gnomad SAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.328

Gnomad OTH exome

AF:

0.341

GnomAD4 exome

AF:

0.339

AC:

491244

AN:

1448634

Hom.:

85322

Cov.:

AF XY:

0.336

AC XY:

242470

AN XY:

721018

show subpopulations

Gnomad4 AFR exome

AF:

0.245

Gnomad4 AMR exome

AF:

0.524

Gnomad4 ASJ exome

AF:

0.306

Gnomad4 EAS exome

AF:

0.380

Gnomad4 SAS exome

AF:

0.279

Gnomad4 FIN exome

AF:

0.375

Gnomad4 NFE exome

AF:

0.337

Gnomad4 OTH exome

AF:

0.340

GnomAD4 genome

AF:

0.323

AC:

49121

AN:

151994

Hom.:

8295

Cov.:

AF XY:

0.328

AC XY:

24344

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.256

Gnomad4 AMR

AF:

0.415

Gnomad4 ASJ

AF:

0.303

Gnomad4 EAS

AF:

0.427

Gnomad4 SAS

AF:

0.280

Gnomad4 FIN

AF:

0.384

Gnomad4 NFE

AF:

0.332

Gnomad4 OTH

AF:

0.301

Alfa

AF:

0.279

Hom.:

1545

Bravo

AF:

0.325

Asia WGS

AF:

0.370

AC:

1286

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2018

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

Immunodeficiency, common variable, 12

Benign:1

Sep 05, 2021

Genome-Nilou Lab

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

-0.91

CADD

Benign

0.20

DANN

Benign

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over