rs4648072

Positions:

chr4-102597543-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_003998.4(NFKB1):c.1519A>G(p.Met507Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,613,440 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 70 hom. )

Consequence

NFKB1
NM_003998.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.289

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 made for transcript

Verdict is Benign. Variant got -19 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=0.0024580657).

BP6

Variant 4-102597543-A-G is Benign according to our data. Variant chr4-102597543-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445400.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 = 0.0176 (2681/152342) while in subpopulation AFR AF= 0.0444 (1845/41578). AF 95% confidence interval is 0.0427. There are 40 homozygotes in gnomad4. There are 1280 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2681 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4 linkuse as main transcript	c.1519A>G	p.Met507Val	missense_variant	15/24	ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9 linkuse as main transcript	c.1519A>G	p.Met507Val	missense_variant	15/24	1	NM_003998.4	P4	P19838-2

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2680

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0445

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00797

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00851

AC:

2131

AN:

250546

Hom.:

AF XY:

0.00772

AC XY:

1045

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.0425

Gnomad AMR exome

AF:

0.00345

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00243

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.00738

Gnomad OTH exome

AF:

0.00722

GnomAD4 exome

AF:

0.00732

AC:

10695

AN:

1461098

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

5200

AN XY:

726786

show subpopulations

Gnomad4 AFR exome

AF:

0.0450

Gnomad4 AMR exome

AF:

0.00381

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00299

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.00658

Gnomad4 OTH exome

AF:

0.00775

GnomAD4 genome

AF:

0.0176

AC:

2681

AN:

152342

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1280

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0444

Gnomad4 AMR

AF:

0.00588

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.0126

Gnomad4 NFE

AF:

0.00798

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00965

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.0411

AC:

181

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00973

AC:

1181

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00624

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 12

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 12, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 28, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.7

DANN

Benign

0.58

DEOGEN2

Benign

0.19

.;T;T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.71

T;.;T;T

MetaRNN

Benign

0.0025

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;L;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

N;N;N;.

REVEL

Benign

0.083

Sift

Benign

0.31

T;T;T;.

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.041

B;B;B;.

Vest4

0.083

MVP

0.38

MPC

0.39

ClinPred

0.0012

GERP RS

-4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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