4-102593501-T-C

Variant names:

• chr4-102593501-T-C
• rs1609993
• NM_003998.4:c.1143T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -7.17
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 12

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1170076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.1143T>C	p.Ala381Ala	synonymous	Exon 12 of 24	NP_003989.2
	NFKB1	NM_001382625.1		c.1143T>C	p.Ala381Ala	synonymous	Exon 13 of 25	NP_001369554.1
	NFKB1	NM_001382626.1		c.1143T>C	p.Ala381Ala	synonymous	Exon 13 of 25	NP_001369555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.1143T>C	p.Ala381Ala	synonymous	Exon 12 of 24	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.1140T>C	p.Ala380Ala	synonymous	Exon 12 of 24	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.1140T>C	p.Ala380Ala	synonymous	Exon 12 of 24	ENSP00000424790.1

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

GnomAD2 exomes AF: 0.940 AC: 236090 AN: 251212 AF XY: 0.940

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 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

African (AFR) AF: 0.989 AC: 33084 AN: 33466

American (AMR) AF: 0.953 AC: 42620 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 23211 AN: 26106

East Asian (EAS) AF: 1.00 AC: 39676 AN: 39686

South Asian (SAS) AF: 0.984 AC: 84865 AN: 86222

European-Finnish (FIN) AF: 0.928 AC: 49575 AN: 53406

Middle Eastern (MID) AF: 0.933 AC: 5373 AN: 5758

European-Non Finnish (NFE) AF: 0.922 AC: 1025243 AN: 1111528

Other (OTH) AF: 0.933 AC: 56304 AN: 60370

GnomAD4 genome AF: 0.944 AC: 143652 AN: 152174 Hom.: 67896 Cov.: 30 AF XY: 0.946 AC XY: 70375 AN XY: 74388

African (AFR) AF: 0.986 AC: 40919 AN: 41508

American (AMR) AF: 0.935 AC: 14279 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3100 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5176

South Asian (SAS) AF: 0.985 AC: 4754 AN: 4824

European-Finnish (FIN) AF: 0.930 AC: 9838 AN: 10574

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.918 AC: 62452 AN: 68024

Other (OTH) AF: 0.934 AC: 1975 AN: 2114

Alfa AF: 0.925 Hom.: 48024

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

Submissions by phenotype

not provided Benign:3

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.094
DANN	Benign	0.27
PhyloP100		-7.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1609993; hg19: chr4-103514658; COSMIC: COSV108088592;