rs4648049

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003998.4(NFKB1):c.1210+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,603,918 control chromosomes in the GnomAD database, including 2,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 406 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1640 hom. )

Consequence

NFKB1
NM_003998.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.05

Publications

6 publications found

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 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

NFKB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 4-102593580-C-T is Benign according to our data. Variant chr4-102593580-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0651

AC:

9902

AN:

152052

Hom.:

401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0373

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.0504

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0654

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0453

Gnomad OTH

AF:

0.0518

GnomAD2 exomes

AF:

0.0462

AC:

11217

AN:

243016

AF XY:

0.0447

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.0198

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.0630

Gnomad FIN exome

AF:

0.0619

Gnomad NFE exome

AF:

0.0462

Gnomad OTH exome

AF:

0.0413

GnomAD4 exome

AF:

0.0448

AC:

65026

AN:

1451748

Hom.:

1640

Cov.:

AF XY:

0.0443

AC XY:

31985

AN XY:

722378

show subpopulations

African (AFR)

AF:

0.123

AC:

3999

AN:

32628

American (AMR)

AF:

0.0212

AC:

908

AN:

42892

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

293

AN:

25720

East Asian (EAS)

AF:

0.0517

AC:

2045

AN:

39536

South Asian (SAS)

AF:

0.0280

AC:

2374

AN:

84872

European-Finnish (FIN)

AF:

0.0618

AC:

3286

AN:

53164

Middle Eastern (MID)

AF:

0.0258

AC:

146

AN:

5660

European-Non Finnish (NFE)

AF:

0.0444

AC:

49222

AN:

1107452

Other (OTH)

AF:

0.0460

AC:

2753

AN:

59824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2630

5260

7891

10521

13151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1864

3728

5592

7456

9320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0653

AC:

9940

AN:

152170

Hom.:

406

Cov.:

AF XY:

0.0657

AC XY:

4887

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.119

AC:

4948

AN:

41496

American (AMR)

AF:

0.0372

AC:

569

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.0500

AC:

259

AN:

5184

South Asian (SAS)

AF:

0.0346

AC:

167

AN:

4824

European-Finnish (FIN)

AF:

0.0654

AC:

692

AN:

10586

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0453

AC:

3083

AN:

68010

Other (OTH)

AF:

0.0513

AC:

108

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

463

925

1388

1850

2313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0499

Hom.:

Bravo

AF:

0.0667

Asia WGS

AF:

0.0540

AC:

186

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.054

(source)

DANN

Benign

0.40

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over