4-102510933-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001382625.1(NFKB1):c.-24A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,285,530 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 47 hom. )

Consequence

NFKB1
NM_001382625.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.405

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 was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.006662905).

BP6

Variant 4-102510933-A-G is Benign according to our data. Variant chr4-102510933-A-G is described in ClinVar as [Benign]. Clinvar id is 1675952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00489 (744/152282) while in subpopulation NFE AF = 0.00853 (580/68030). AF 95% confidence interval is 0.00795. There are 3 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 744 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4 link	c.-8+9145A>G		intron_variant	Intron 1 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.-8+9145A>G		intron_variant	Intron 1 of 23	1	NM_003998.4	ENSP00000226574.4		P19838-2
NFKB1	ENST00000505458.5 link	c.-8+8766A>G		intron_variant	Intron 1 of 23	1		ENSP00000424790.1		P19838-1

Frequencies

GnomAD3 genomes

AF:

0.00489

AC:

744

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00852

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00400

AC:

509

AN:

127208

AF XY:

0.00396

show subpopulations

Gnomad AFR exome

AF:

0.00165

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00487

Gnomad NFE exome

AF:

0.00811

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00778

AC:

8817

AN:

1133248

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

4207

AN XY:

556046

show subpopulations

African (AFR)

AF:

0.000949

AC:

AN:

24226

American (AMR)

AF:

0.00118

AC:

AN:

27938

Ashkenazi Jewish (ASJ)

AF:

0.000127

AC:

AN:

15790

East Asian (EAS)

AF:

0.00

AC:

AN:

12810

South Asian (SAS)

AF:

0.00199

AC:

151

AN:

75756

European-Finnish (FIN)

AF:

0.00531

AC:

AN:

12428

Middle Eastern (MID)

AF:

0.000686

AC:

AN:

4374

European-Non Finnish (NFE)

AF:

0.00907

AC:

8336

AN:

918618

Other (OTH)

AF:

0.00491

AC:

203

AN:

41308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

395

791

1186

1582

1977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00489

AC:

744

AN:

152282

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

346

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41558

American (AMR)

AF:

0.00203

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00187

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00650

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00853

AC:

580

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00683

Hom.:

Bravo

AF:

0.00410

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00960

AC:

ExAC

AF:

0.00190

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NFKB1: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.9

(source)

DANN

Benign

0.58

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.012

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-0.98

PhyloP100

0.41

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.074

Sift

Pathogenic

0.0

D;D

MVP

0.28

ClinPred

0.042

GERP RS

-2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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4-102510933-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over