NM_003998.4:c.1469C>T

Variant names:

Variant summary

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

The NM_003998.4(NFKB1):c.1469C>T(p.Thr490Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,610,464 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

NFKB1
NM_003998.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.51

Publications

12 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 (MetaRNN=0.00436458).

BP6

Variant 4-102596306-C-T is Benign according to our data. Variant chr4-102596306-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 790005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00251 (382/152294) while in subpopulation AFR AF = 0.00852 (354/41568). AF 95% confidence interval is 0.00779. There are 2 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 382 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4 link	c.1469C>T	p.Thr490Ile	missense_variant	Exon 14 of 24	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.1469C>T	p.Thr490Ile	missense_variant	Exon 14 of 24	1	NM_003998.4	ENSP00000226574.4		P19838-2
NFKB1	ENST00000505458.5 link	c.1466C>T	p.Thr489Ile	missense_variant	Exon 14 of 24	1		ENSP00000424790.1		P19838-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

381

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00852

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000761

AC:

190

AN:

249534

AF XY:

0.000548

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000324

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000271

AC:

395

AN:

1458170

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

162

AN XY:

725440

show subpopulations

African (AFR)

AF:

0.00991

AC:

331

AN:

33392

American (AMR)

AF:

0.000384

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109680

Other (OTH)

AF:

0.000681

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00251

AC:

382

AN:

152294

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00852

AC:

354

AN:

41568

American (AMR)

AF:

0.00163

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000989

Hom.:

Bravo

AF:

0.00273

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000840

AC:

102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NFKB1: BP4, BS1 -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.036

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.15

.;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.36

T;.;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N;.

PhyloP100

-1.5

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.29

N;N;N;.

REVEL

Benign

0.014

Sift

Benign

0.23

T;T;T;.

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.063

MVP

0.16

MPC

0.41

ClinPred

0.0058

GERP RS

-9.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.015

gMVP

0.15

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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