Variant rs966015688 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003998.4(NFKB1):c.47A>G(p.His16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NFKB1
NM_003998.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0190

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047943413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4 link	c.47A>G	p.His16Arg	missense_variant	Exon 3 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.47A>G	p.His16Arg	missense_variant	Exon 3 of 24	1	NM_003998.4	ENSP00000226574.4		P19838-2
NFKB1	ENST00000505458.5 link	c.47A>G	p.His16Arg	missense_variant	Exon 3 of 24	1		ENSP00000424790.1		P19838-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

244106

Hom.:

AF XY:

0.00000758

AC XY:

AN XY:

132002

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447366

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720454

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.6

DANN

Benign

0.97

DEOGEN2

Benign

0.18

.;T;.;.;T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.69

T;.;T;T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.048

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;.;.;L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.71

N;N;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.12

T;T;T;T;T;T

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.085

B;B;.;.;B;.

Vest4

0.26

MutPred

0.25

Loss of catalytic residue at D18 (P = 0.1104);Loss of catalytic residue at D18 (P = 0.1104);.;.;Loss of catalytic residue at D18 (P = 0.1104);Loss of catalytic residue at D18 (P = 0.1104);

MVP

0.41

MPC

1.3

ClinPred

0.045

GERP RS

0.47

Varity_R

0.066

gMVP

0.50

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over