rs869320688

Variant names:

• chr4-102579043-A-G
• rs869320688
• NM_003998.4:c.730+4A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PP3_Moderate PP5_Moderate

The NM_003998.4(NFKB1):​c.730+4A>G variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002768980: Both EBV cell lines transformed with patient lymphocytes and HEK293T cells transfected with the mutant construct demonstrated weak expression of the precursor mutant protein (p105delEx8) and none of the processed p50delEx8, suggesting that the mutant protein is degraded and resulting in p50 haploinsufficiency (PMID:26279205).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKB1 NM_003998.4 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.97
• Publications: 5 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: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002768980: Both EBV cell lines transformed with patient lymphocytes and HEK293T cells transfected with the mutant construct demonstrated weak expression of the precursor mutant protein (p105delEx8) and none of the processed p50delEx8, suggesting that the mutant protein is degraded and resulting in p50 haploinsufficiency (PMID: 26279205).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-102579043-A-G is Pathogenic according to our data. Variant chr4-102579043-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 210056.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.730+4A>G		splice_region intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.730+4A>G		splice_region intron	N/A	NP_001369554.1	P19838-2
	NFKB1	NM_001382626.1		c.730+4A>G		splice_region intron	N/A	NP_001369555.1	P19838-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.730+4A>G		splice_region intron	N/A	ENSP00000226574.4	P19838-2
	NFKB1	ENST00000394820.8	TSL:1	c.727+4A>G		splice_region intron	N/A	ENSP00000378297.4	P19838-1
	NFKB1	ENST00000505458.5	TSL:1	c.727+4A>G		splice_region intron	N/A	ENSP00000424790.1	P19838-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Immunodeficiency, common variable, 12 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.96
PhyloP100		9.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -29
DS_DL_spliceai		0.58		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869320688; hg19: chr4-103500200;