4-102615513-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003998.4(NFKB1):​c.2750-921A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 152,320 control chromosomes in the GnomAD database, including 689 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.083 ( 689 hom., cov: 33)

Consequence

NFKB1
NM_003998.4 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.20

Publications

26 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NFKB1NM_003998.4 linkc.2750-921A>G intron_variant Intron 23 of 23 ENST00000226574.9 NP_003989.2 P19838-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NFKB1ENST00000226574.9 linkc.2750-921A>G intron_variant Intron 23 of 23 1 NM_003998.4 ENSP00000226574.4 P19838-2
NFKB1ENST00000505458.5 linkc.2747-921A>G intron_variant Intron 23 of 23 1 ENSP00000424790.1 P19838-1

Frequencies

GnomAD3 genomes
AF:
0.0827
AC:
12589
AN:
152202
Hom.:
689
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.161
Gnomad AMI
AF:
0.0702
Gnomad AMR
AF:
0.0442
Gnomad ASJ
AF:
0.0181
Gnomad EAS
AF:
0.0639
Gnomad SAS
AF:
0.0364
Gnomad FIN
AF:
0.0781
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.0534
Gnomad OTH
AF:
0.0611
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.0828
AC:
12615
AN:
152320
Hom.:
689
Cov.:
33
AF XY:
0.0817
AC XY:
6089
AN XY:
74492
show subpopulations
African (AFR)
AF:
0.161
AC:
6704
AN:
41550
American (AMR)
AF:
0.0441
AC:
675
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.0181
AC:
63
AN:
3472
East Asian (EAS)
AF:
0.0636
AC:
330
AN:
5186
South Asian (SAS)
AF:
0.0371
AC:
179
AN:
4830
European-Finnish (FIN)
AF:
0.0781
AC:
830
AN:
10626
Middle Eastern (MID)
AF:
0.0272
AC:
8
AN:
294
European-Non Finnish (NFE)
AF:
0.0534
AC:
3634
AN:
68026
Other (OTH)
AF:
0.0605
AC:
128
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
584
1168
1753
2337
2921
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
130
260
390
520
650
<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:
0.0537
Hom.:
493
Bravo
AF:
0.0843
Asia WGS
AF:
0.0540
AC:
189
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.92
CADD
Benign
0.034
DANN
Benign
0.24
PhyloP100
-2.2
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

Publications

Other links and lift over

dbSNP: rs4648135; hg19: chr4-103536670; API