chr4-102593584-T-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.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

Publications

15 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:

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=-0.91).

BP6

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

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 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.1210+16T>C	intron	N/A	NP_003989.2
NFKB1	NM_001382625.1		c.1210+16T>C	intron	N/A	NP_001369554.1	P19838-2
NFKB1	NM_001382626.1		c.1210+16T>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.1210+16T>C	intron	N/A	ENSP00000226574.4	P19838-2
NFKB1	ENST00000394820.8	TSL:1	c.1207+16T>C	intron	N/A	ENSP00000378297.4	P19838-1
NFKB1	ENST00000505458.5	TSL:1	c.1207+16T>C	intron	N/A	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

GnomAD2 exomes

AF:

0.358

AC:

87122

AN:

243112

AF XY:

0.349

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 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

African (AFR)

AF:

0.245

AC:

7992

AN:

32578

American (AMR)

AF:

0.524

AC:

22353

AN:

42652

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

7846

AN:

25650

East Asian (EAS)

AF:

0.380

AC:

15006

AN:

39480

South Asian (SAS)

AF:

0.279

AC:

23577

AN:

84628

European-Finnish (FIN)

AF:

0.375

AC:

19908

AN:

53050

Middle Eastern (MID)

AF:

0.288

AC:

1628

AN:

5644

European-Non Finnish (NFE)

AF:

0.337

AC:

372643

AN:

1105238

Other (OTH)

AF:

0.340

AC:

20291

AN:

59714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

13839

27678

41516

55355

69194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12240

24480

36720

48960

61200

<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:

0.323

AC:

49121

AN:

151994

Hom.:

8295

Cov.:

AF XY:

0.328

AC XY:

24344

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.256

AC:

10617

AN:

41488

American (AMR)

AF:

0.415

AC:

6351

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1050

AN:

3464

East Asian (EAS)

AF:

0.427

AC:

2205

AN:

5168

South Asian (SAS)

AF:

0.280

AC:

1352

AN:

4820

European-Finnish (FIN)

AF:

0.384

AC:

4038

AN:

10514

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.332

AC:

22528

AN:

67938

Other (OTH)

AF:

0.301

AC:

635

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1647

3294

4941

6588

8235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.278

Hom.:

1574

Bravo

AF:

0.325

Asia WGS

AF:

0.370

AC:

1286

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Immunodeficiency, common variable, 12 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.20

(source)

DANN

Benign

0.46

PhyloP100

-0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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