4-102593501-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003998.4(NFKB1):c.1143T>C(p.Ala381=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.17

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]

ACMG classification

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/exons	MANE	UniProt
NFKB1	NM_003998.4	c.1143T>C	p.Ala381=	synonymous_variant	12/24	ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.1143T>C	p.Ala381=	synonymous_variant	12/24	1	NM_003998.4	P4

Frequencies

GnomAD3 genomes AF: 0.944 AC: 143529 AN: 152056 Hom.: 67832 Cov.: 30

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

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.: 41 AF XY: 0.932 AC XY: 677287 AN XY: 726988

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.: 30 AF XY: 0.946 AC XY: 70375 AN XY: 74388

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

Other links and lift over

dbSNP: rs1609993; hg19: chr4-103514658;