NM_003998.4:c.1954+22T>C

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.1954+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 1,601,214 control chromosomes in the GnomAD database, including 1,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 282 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1528 hom. )

Consequence

NFKB1
NM_003998.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.505

Publications

19 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: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NFKB1 links:

ENSG00000304360 (HGNC:58861):

ENSG00000304360 links:

LOC105377347 (HGNC:):

LOC105377347 links:

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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=-0.9).

BP6

Variant 4-102606719-T-C is Benign according to our data. Variant chr4-102606719-T-C is described in ClinVar as Benign. ClinVar VariationId is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0863 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFKB1	NM_003998.4	MANE Select	c.1954+22T>C	intron	N/A	NP_003989.2
NFKB1	NM_001382625.1		c.1954+22T>C	intron	N/A	NP_001369554.1	P19838-2
NFKB1	NM_001382626.1		c.1954+22T>C	intron	N/A	NP_001369555.1	P19838-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.1954+22T>C	intron	N/A	ENSP00000226574.4	P19838-2
NFKB1	ENST00000394820.8	TSL:1	c.1951+22T>C	intron	N/A	ENSP00000378297.4	P19838-1
NFKB1	ENST00000505458.5	TSL:1	c.1951+22T>C	intron	N/A	ENSP00000424790.1	P19838-1

Frequencies

GnomAD3 genomes

AF:

0.0571

AC:

8688

AN:

152160

Hom.:

282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0887

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0351

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0630

Gnomad SAS

AF:

0.0346

Gnomad FIN

AF:

0.0655

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0478

GnomAD2 exomes

AF:

0.0460

AC:

10932

AN:

237908

AF XY:

0.0451

show subpopulations

Gnomad AFR exome

AF:

0.0902

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.0778

Gnomad FIN exome

AF:

0.0625

Gnomad NFE exome

AF:

0.0474

Gnomad OTH exome

AF:

0.0409

GnomAD4 exome

AF:

0.0445

AC:

64487

AN:

1448936

Hom.:

1528

Cov.:

AF XY:

0.0441

AC XY:

31763

AN XY:

719584

show subpopulations

African (AFR)

AF:

0.0939

AC:

3124

AN:

33258

American (AMR)

AF:

0.0200

AC:

873

AN:

43566

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

298

AN:

25926

East Asian (EAS)

AF:

0.0586

AC:

2312

AN:

39452

South Asian (SAS)

AF:

0.0290

AC:

2477

AN:

85468

European-Finnish (FIN)

AF:

0.0620

AC:

3293

AN:

53120

Middle Eastern (MID)

AF:

0.0249

AC:

143

AN:

5750

European-Non Finnish (NFE)

AF:

0.0447

AC:

49270

AN:

1102490

Other (OTH)

AF:

0.0450

AC:

2697

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

3276

6553

9829

13106

16382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1854

3708

5562

7416

9270

<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:

0.0571

AC:

8701

AN:

152278

Hom.:

282

Cov.:

AF XY:

0.0570

AC XY:

4245

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0887

AC:

3686

AN:

41550

American (AMR)

AF:

0.0350

AC:

536

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.0625

AC:

324

AN:

5180

South Asian (SAS)

AF:

0.0353

AC:

170

AN:

4822

European-Finnish (FIN)

AF:

0.0655

AC:

695

AN:

10612

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0453

AC:

3078

AN:

68020

Other (OTH)

AF:

0.0473

AC:

100

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

427

854

1282

1709

2136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0460

Hom.:

Bravo

AF:

0.0571

Asia WGS

AF:

0.0500

AC:

173

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.073

(source)

DANN

Benign

0.57

PhyloP100

0.51

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over