rs869320688
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_003998.4(NFKB1):c.730+4A>G variant causes a splice donor 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. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
NFKB1
NM_003998.4 splice_donor_region, intron
NM_003998.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 8.97
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius 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 id is 210056.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-102579043-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NFKB1 | NM_003998.4 | c.730+4A>G | splice_donor_region_variant, intron_variant | ENST00000226574.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NFKB1 | ENST00000226574.9 | c.730+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_003998.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Immunodeficiency, common variable, 12 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 03, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with common variable immunodeficiency 12 (MIM# 616576). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance is estimated to be 60%, with some carriers appearing asymptomatic (PMID: 29477724). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to result in an in-frame deletion of exon 8 (p.(Asp191_Lys244delinsGlu)). 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). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable non-canonical splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported as pathogenic in LOVD with no supporting information. In addition, this variant has been shown to segregate in at least ten affected individuals within the family of this proband; however five individuals presenting with hypogammaglobulinaemia did not have this variant (PMID: 26279205). Lastly, a substitution on the adjacent nucleotide, c.730+5G>A, resulting in the same protein consequence as our variant, c.730+4A>G, has recently been reported in one individual with pyoderma gangrenosum (PMID: 34447408). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -29
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at