4-102537668-A-G

Variant names:

• chr4-102537668-A-G
• rs230526
• NM_003998.4:c.160-190A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003998.4(NFKB1):​c.160-190A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 467,118 control chromosomes in the GnomAD database, including 86,015 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26379 hom., cov: 31)
  • Exomes 𝑓: 0.61 (59636 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.282
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-102537668-A-G is Benign according to our data. Variant chr4-102537668-A-G is described in ClinVar as Benign. ClinVar VariationId is 1290273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.676 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.160-190A>G		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.160-190A>G		intron	N/A	NP_001369554.1
	NFKB1	NM_001382626.1		c.160-190A>G		intron	N/A	NP_001369555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.160-190A>G		intron	N/A	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.157-190A>G		intron	N/A	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.157-190A>G		intron	N/A	ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89188 AN: 151838 Hom.: 26369 Cov.: 31

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.607

GnomAD4 exome AF: 0.610 AC: 192208 AN: 315162 Hom.: 59636 Cov.: 3 AF XY: 0.615 AC XY: 103247 AN XY: 167770

African (AFR) AF: 0.593 AC: 5278 AN: 8904

American (AMR) AF: 0.473 AC: 5983 AN: 12658

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 6357 AN: 9600

East Asian (EAS) AF: 0.579 AC: 12263 AN: 21162

South Asian (SAS) AF: 0.708 AC: 23747 AN: 33540

European-Finnish (FIN) AF: 0.577 AC: 12149 AN: 21064

Middle Eastern (MID) AF: 0.691 AC: 953 AN: 1380

European-Non Finnish (NFE) AF: 0.608 AC: 114625 AN: 188624

Other (OTH) AF: 0.595 AC: 10853 AN: 18230

GnomAD4 genome AF: 0.587 AC: 89222 AN: 151956 Hom.: 26379 Cov.: 31 AF XY: 0.585 AC XY: 43428 AN XY: 74258

African (AFR) AF: 0.582 AC: 24111 AN: 41418

American (AMR) AF: 0.519 AC: 7926 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2293 AN: 3466

East Asian (EAS) AF: 0.526 AC: 2717 AN: 5168

South Asian (SAS) AF: 0.696 AC: 3359 AN: 4826

European-Finnish (FIN) AF: 0.548 AC: 5771 AN: 10530

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40970 AN: 67960

Other (OTH) AF: 0.611 AC: 1291 AN: 2112

Alfa AF: 0.602 Hom.: 20564

Bravo AF: 0.581

Asia WGS AF: 0.582 AC: 2026 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

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	-0.79
CADD	Benign	3.3
DANN	Benign	0.66
PhyloP100		0.28
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: rs230526; hg19: chr4-103458825;