4-102593501-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003998.4(NFKB1):c.1143T>C(p.Ala381Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 1,613,432 control chromosomes in the GnomAD database, including 701,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 67896 hom., cov: 30)

Exomes 𝑓: 0.93 ( 633219 hom. )

Consequence

NFKB1
NM_003998.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -7.17

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 4-102593501-T-C is Benign according to our data. Variant chr4-102593501-T-C is described in ClinVar as [Benign]. Clinvar id is 1170076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102593501-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-7.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4 link	c.1143T>C	p.Ala381Ala	synonymous_variant	Exon 12 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.1143T>C	p.Ala381Ala	synonymous_variant	Exon 12 of 24	1	NM_003998.4	ENSP00000226574.4		P19838-2
NFKB1	ENST00000505458.5 link	c.1140T>C	p.Ala380Ala	synonymous_variant	Exon 12 of 24	1		ENSP00000424790.1		P19838-1

Frequencies

GnomAD3 genomes

AF:

0.944

AC:

143529

AN:

152056

Hom.:

67832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.986

Gnomad AMI

AF:

0.977

Gnomad AMR

AF:

0.934

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.985

Gnomad FIN

AF:

0.930

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.918

Gnomad OTH

AF:

0.934

GnomAD3 exomes

AF:

0.940

AC:

236090

AN:

251212

Hom.:

111093

AF XY:

0.940

AC XY:

127592

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.988

Gnomad AMR exome

AF:

0.956

Gnomad ASJ exome

AF:

0.885

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.985

Gnomad FIN exome

AF:

0.931

Gnomad NFE exome

AF:

0.914

Gnomad OTH exome

AF:

0.925

GnomAD4 exome

AF:

0.931

AC:

1359951

AN:

1461258

Hom.:

633219

Cov.:

AF XY:

0.932

AC XY:

677287

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.989

Gnomad4 AMR exome

AF:

0.953

Gnomad4 ASJ exome

AF:

0.889

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.984

Gnomad4 FIN exome

AF:

0.928

Gnomad4 NFE exome

AF:

0.922

Gnomad4 OTH exome

AF:

0.933

GnomAD4 genome

AF:

0.944

AC:

143652

AN:

152174

Hom.:

67896

Cov.:

AF XY:

0.946

AC XY:

70375

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.986

Gnomad4 AMR

AF:

0.935

Gnomad4 ASJ

AF:

0.893

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.985

Gnomad4 FIN

AF:

0.930

Gnomad4 NFE

AF:

0.918

Gnomad4 OTH

AF:

0.934

Alfa

AF:

0.925

Hom.:

43029

Bravo

AF:

0.943

Asia WGS

AF:

0.991

AC:

3445

AN:

3478

EpiCase

AF:

0.915

EpiControl

AF:

0.910

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 87. Only high quality variants are reported. -

Immunodeficiency, common variable, 12

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.094

DANN

Benign

0.27

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