ClinVar Genomic variation as it relates to human health
NM_000022.4(ADA):c.219-2A>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_000022.4(ADA):c.219-2A>G
Variation ID: 1969 Accession: VCV000001969.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.12 20: 44626601 (GRCh38) [ NCBI UCSC ] 20: 43255242 (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 Apr 4, 2013 Feb 14, 2024 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000022.4:c.219-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001322050.2:c.-71-2A>G splice acceptor NM_001322051.2:c.219-2A>G splice acceptor NC_000020.11:g.44626601T>C NC_000020.10:g.43255242T>C NG_007385.1:g.30135A>G LRG_16:g.30135A>G LRG_16t1:c.219-2A>G - Protein change
- Other names
- IVS3AS, A-G, -2, EX4DEL
- Canonical SPDI
- NC_000020.11:44626600:T:C
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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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ADA | - | - |
GRCh38 GRCh37 |
521 | 673 |
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
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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 (5) |
reviewed by expert panel
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Nov 14, 2023 | RCV000002046.5 |
Submissions - Germline
Classification
Help
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
(Nov 14, 2023)
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reviewed by expert panel
Method: curation
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Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Accession: SCV004102820.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NM_000022.4:c.219-2A>G variant in ADA occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant … (more)
The NM_000022.4:c.219-2A>G variant in ADA occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4, resulting in an in-frame deletion (removes amino acids 74-121), and the prediction is confirmed by RT-PCR (PMID 3182793). The variant removes >10% of the protein (48/363 amino acids) and the truncated region is critical to protein function (PMID 3182793) (PVS1_Strong). The variant has been detected in 1 individual with SCID who was homozygous for this variant (PMID 28266921) (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Strong, PM3_Supporting, PM2_Supporting. (VCEP specifications version 1). (less)
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Likely pathogenic
(Oct 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791443.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Nov 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004217504.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004298089.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 1969). This variant is also known as 24971A>G. Disruption of this splice site has been observed … (more)
ClinVar contains an entry for this variant (Variation ID: 1969). This variant is also known as 24971A>G. Disruption of this splice site has been observed in individual(s) with ADA-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 of the ADA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a premature termination codon (PMID: 3182793, 3475710). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 05, 1988)
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no assertion criteria provided
Method: literature only
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SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022204.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with SCID due to ADA deficiency (102700), Akeson et al. (1987) identified compound heterozygosity for 2 mutations in the ADA gene: a … (more)
In a patient with SCID due to ADA deficiency (102700), Akeson et al. (1987) identified compound heterozygosity for 2 mutations in the ADA gene: a deletion of exon 4 and A329V (608958.0006). Akeson et al. (1988) found that the exon 4 deletion was caused by an A-to-G transition in the 3-prime splice site of intron 3. Functional expression studies showed that the mutant gene was transcribed into normal mRNA but did not encode a functional protein. (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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Clinical, Laboratory, and Molecular Findings for 63 Patients With Severe Combined Immunodeficiency: A Decade´s Experience. | Fazlollahi MR | Journal of investigational allergology & clinical immunology | 2017 | PMID: 28266921 |
Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts. | Akeson AL | The Journal of biological chemistry | 1988 | PMID: 3182793 |
Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing. | Akeson AL | Proceedings of the National Academy of Sciences of the United States of America | 1987 | PMID: 3475710 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/07d338de-c55f-43ab-bb35-f53075f9e0a3 | - | - | - | - |
Text-mined citations for rs387906267 ...
HelpRecord last updated Feb 14, 2024
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.