4-102529863-C-G

Position:

chr4-102529863-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_003998.4(NFKB1):c.67C>G(p.His23Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NFKB1
NM_003998.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.619

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:

NFKB1 (HGNC:):

NFKB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFKB1. . Gene score misZ 3.1933 (greater than the threshold 3.09). Trascript score misZ 3.9653 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency, common variable, 12, common variable immunodeficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.074858695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB1	NM_003998.4 linkuse as main transcript	c.67C>G	p.His23Asp	missense_variant	3/24	ENST00000226574.9	NP_003989.2	P19838-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9 linkuse as main transcript	c.67C>G	p.His23Asp	missense_variant	3/24	1	NM_003998.4	ENSP00000226574.4		P19838-2
NFKB1	ENST00000505458.5 linkuse as main transcript	c.67C>G	p.His23Asp	missense_variant	3/24	1		ENSP00000424790.1		P19838-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247762

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134038

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1456502

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724708

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NFKB1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 23 of the NFKB1 protein (p.His23Asp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;.;.;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.72

T;.;T;T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.075

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;.;.;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.24

N;N;N;N;N;N

REVEL

Benign

0.027

Sift

Benign

0.043

D;T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T;T

Polyphen

0.16

B;B;.;.;B;.

Vest4

0.33

MutPred

0.20

Gain of disorder (P = 0.067);Gain of disorder (P = 0.067);.;.;Gain of disorder (P = 0.067);Gain of disorder (P = 0.067);

MVP

0.48

MPC

1.6

ClinPred

0.040

GERP RS

2.9

Varity_R

0.068

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over