Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11524731, 9921903, 17220063, 35753512)
ClinVar Genomic variation as it relates to human health
NM_000383.4(AIRE):c.463+2T>C
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000383.4(AIRE):c.463+2T>C
Variation ID: 188800 Accession: VCV000188800.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 44287135 (GRCh38) [ NCBI UCSC ] 21: 45707018 (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 Mar 29, 2015 Feb 14, 2024 Oct 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000383.4:c.463+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000021.9:g.44287135T>C NC_000021.8:g.45707018T>C NG_009556.1:g.6256T>C LRG_18:g.6256T>C LRG_18t1:c.463+2T>C - Protein change
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- Other names
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- Canonical SPDI
- NC_000021.9:44287134: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| AIRE | - | - |
GRCh38 GRCh37 |
1134 | 1275 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV000169131.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2023 | RCV000413548.3 |
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
Help
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
Help
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
Help
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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|---|---|---|---|---|---|
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Likely pathogenic
(May 21, 2014)
|
criteria provided, single submitter
Method: literature only
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Polyglandular autoimmune syndrome, type 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220341.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490397.3
First in ClinVar: Jan 09, 2017 Last updated: Nov 25, 2023 |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more)
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11524731, 9921903, 17220063, 35753512) (less)
|
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Pathogenic
(Jun 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Polyglandular autoimmune syndrome, type 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020595.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: AIRE c.463+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: AIRE c.463+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. The variant allele was found at a frequency of 1.2e-05 in 242240 control chromosomes (gnomAD). c.463+2T>C has been reported in the literature in multiple individuals affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) (examples: Wang_1998, and Dominguez_2006). This variant is also known as 5835T>C. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9921903, 17220063). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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APECED
Affected status: no
Allele origin:
germline
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National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV004036179.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
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Pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Polyglandular autoimmune syndrome, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001408348.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 3 of the AIRE gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 3 of the AIRE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs786204478, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9921903, 17220063). This variant is also known as 5835T>C and IVS3+2T>C. ClinVar contains an entry for this variant (Variation ID: 188800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 09, 2020)
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no assertion criteria provided
Method: clinical testing
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Polyglandular autoimmune syndrome type 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083854.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Variant summary: AIRE c.463+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. The variant allele was found at a frequency of 1.2e-05 in 242240 control chromosomes (gnomAD). c.463+2T>C has been reported in the literature in multiple individuals affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) (examples: Wang_1998, and Dominguez_2006). This variant is also known as 5835T>C. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9921903, 17220063). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change affects a donor splice site in intron 3 of the AIRE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs786204478, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9921903, 17220063). This variant is also known as 5835T>C and IVS3+2T>C. ClinVar contains an entry for this variant (Variation ID: 188800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11524731, 9921903, 17220063, 35753512)
Comment:
Variant summary: AIRE c.463+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. The variant allele was found at a frequency of 1.2e-05 in 242240 control chromosomes (gnomAD). c.463+2T>C has been reported in the literature in multiple individuals affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) (examples: Wang_1998, and Dominguez_2006). This variant is also known as 5835T>C. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9921903, 17220063). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change affects a donor splice site in intron 3 of the AIRE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs786204478, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9921903, 17220063). This variant is also known as 5835T>C and IVS3+2T>C. ClinVar contains an entry for this variant (Variation ID: 188800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations. | Similuk MN | The Journal of allergy and clinical immunology | 2022 | PMID: 35753512 |
| Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. | Kisand K | Journal of clinical immunology | 2015 | PMID: 26141571 |
| Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the Irish population. | Dominguez M | Journal of pediatric endocrinology & metabolism : JPEM | 2006 | PMID: 17220063 |
| Ocular complications of autoimmune polyendocrinopathy syndrome type 1. | Chang B | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2006 | PMID: 17189144 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| APECED mutations in the autoimmune regulator (AIRE) gene. | Heino M | Human mutation | 2001 | PMID: 11524731 |
| Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). | Wang CY | Human genetics | 1998 | PMID: 9921903 |
Text-mined citations for rs786204478 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.