ClinVar Genomic variation as it relates to human health
NM_003998.4(NFKB1):c.730+4A>G
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003998.4(NFKB1):c.730+4A>G
Variation ID: 210056 Accession: VCV000210056.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q24 4: 102579043 (GRCh38) [ NCBI UCSC ] 4: 103500200 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 29, 2016 Dec 24, 2022 Feb 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003998.4:c.730+4A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001165412.2:c.727+4A>G intron variant NM_001319226.2:c.727+4A>G intron variant NC_000004.12:g.102579043A>G NC_000004.11:g.103500200A>G NG_050628.1:g.82715A>G LRG_1316:g.82715A>G LRG_1316t1:c.730+4A>G - Protein change
- Other names
- IVS8DS, A-G, +4
- Canonical SPDI
- NC_000004.12:102579042:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NFKB1 | - | - |
GRCh38 GRCh37 |
686 | 728 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Feb 2, 2022 | RCV000192693.5 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 12
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768980.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Sep 03, 2015)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000246276.3
First in ClinVar: Oct 05, 2015 Last updated: Apr 23, 2021 |
Comment on evidence:
In affected members of a large multigenerational Dutch-Australian family (FamNL1) with autosomal dominant common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Fliegauf et al. (2015) identified … (more)
In affected members of a large multigenerational Dutch-Australian family (FamNL1) with autosomal dominant common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Fliegauf et al. (2015) identified a heterozygous c.730+4A-G transition (c.730+4A-G, NM_003998.3) in intron 8 of the NFKB1 gene, resulting in the skipping of exon 8 in variant 1 of the precursor protein. The mutation was predicted to delete an internal fragment from the N-terminal RHD domain (Asp191_Lys244delinsGlu). Western blot analysis of patient cells showed about 50% reduced levels of the p105 and p50 proteins, and only marginal presence of the mutant p105 protein; mutant p50 was not detected. These findings suggested that the mutant p105 protein was not processed to a corresponding truncated p50 protein, resulting in functional haploinsufficiency of NFKB1 subunit p50. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. In vitro functional expression assays in transfected cells showed almost undetectable levels of mutant NFKB1 p105 and p50, suggesting that they are highly unstable and probably nonfunctional. The mutation was found in 10 family members with CVID and in 3 with hypogammaglobulinemia; it was not found in several additional family members who had hypogammaglobulinemia, suggesting that the latter individuals had a phenocopy. The family had previously been reported by Nijenhuis et al. (2001) and Finck et al. (2006). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Case Report: A Novel Mutation in NFKB1 Associated With Pyoderma Gangrenosum. | Fang R | Frontiers in genetics | 2021 | PMID: 34447408 |
Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. | Tuijnenburg P | The Journal of allergy and clinical immunology | 2018 | PMID: 29477724 |
Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. | Fliegauf M | American journal of human genetics | 2015 | PMID: 26279205 |
Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. | Finck A | European journal of human genetics : EJHG | 2006 | PMID: 16639407 |
Common variable immunodeficiency (CVID) in a family: an autosomal dominant mode of inheritance. | Nijenhuis T | The Netherlands journal of medicine | 2001 | PMID: 11583829 |
Text-mined citations for rs869320688 ...
HelpRecord last updated Aug 06, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.