ClinVar Genomic variation as it relates to human health
NM_000213.5(ITGB4):c.3793+1G>A
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_000213.5(ITGB4):c.3793+1G>A
Variation ID: 14736 Accession: VCV000014736.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.1 17: 75751112 (GRCh38) [ NCBI UCSC ] 17: 73747193 (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 Jun 18, 2015 Apr 6, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000213.5:c.3793+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001005619.1:c.3793+1G>A splice donor NM_001005731.2:c.3793+1G>A NM_001005731.3:c.3793+1G>A splice donor NM_001321123.2:c.3793+1G>A splice donor NC_000017.11:g.75751112G>A NC_000017.10:g.73747193G>A NG_007372.1:g.34678G>A NG_007372.2:g.34655G>A NG_008079.2:g.19088C>T LRG_1430:g.19088C>T - Protein change
- Other names
- IVS30DS, G-A, +1
- Canonical SPDI
- NC_000017.11:75751111:G:A
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
Help
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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ITGB4 | - | - |
GRCh38 GRCh37 |
1065 | 1542 |
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
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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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Pathogenic (2) |
criteria provided, single submitter
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Mar 29, 2024 | RCV000015857.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV000255841.3 |
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
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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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Pathogenic
(Mar 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321784.7
First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019 |
Comment:
The c.3793+1G>A: IVS30+1G>A pathogenic variant in the ITGB4 gene has been reported previously in association with EB-PA (Pulkkinen et al. 1997 Mellerio et al., 1998, … (more)
The c.3793+1G>A: IVS30+1G>A pathogenic variant in the ITGB4 gene has been reported previously in association with EB-PA (Pulkkinen et al. 1997 Mellerio et al., 1998, Ashton et al., 2001, Varki et al., 2006, Dang et al. 2008, Lee et al. 2015). Pulkkinen et al. 1997 showed that the variant leads to the use of a cryptic splice site and results in a frameshift and the creation of a downstream STOP codon resulting in premature termination of the protein and when present in the homozygous state results in a severe phenotype (Dang et al., 2008). This splice site variant destroys the canonical splice donor site in intron 30. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.3793+1G>A: IVS30+1G>A variant was not observed in significant numbers in approximately 8600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3793+1G>A: IVS30+1G>A as a pathogenic variant. (less)
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Pathogenic
(Sep 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297542.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs147222357, gnomAD 0.002%). This sequence change affects a donor splice site in intron 30 of the ITGB4 gene. … (more)
This variant is present in population databases (rs147222357, gnomAD 0.002%). This sequence change affects a donor splice site in intron 30 of the ITGB4 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 ITGB4 are known to be pathogenic (PMID: 11328943, 16473856). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 14736). Disruption of this splice site has been observed in individuals with epidermolysis bullosa (PMID: 33937469, 34046686). (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Junctional epidermolysis bullosa with pyloric atresia
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807721.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Nov 01, 1998)
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no assertion criteria provided
Method: literature only
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EPIDERMOLYSIS BULLOSA, JUNCTIONAL 5B, WITH PYLORIC ATRESIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036124.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 02, 2022 |
Comment on evidence:
Mellerio et al. (1998) reported 2 unrelated patients with junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) who survived into early childhood with mild cutaneous … (more)
Mellerio et al. (1998) reported 2 unrelated patients with junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) who survived into early childhood with mild cutaneous involvement. One patient was compound heterozygous for a splice site mutation in exon 30 (3793+1G-A) and a nonsense mutation in exon 36 (W1478X; 147557.0008). The second patient was compound heterozygous with a missense mutation in exon 3 (C38R; 147557.0009) and a 1-bp deletion in exon 36 (4776delG; 147557.0010). Although the nonsense and deletion mutations were predicted to result in markedly reduced beta-4 integrin mRNA levels, the presence of the missense or splice site mutation on the second allele may enable the synthesis of some functional, albeit perturbed, beta-4 polypeptide. (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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Epidermolysis Bullosa in Chinese Patients: Genetic Analysis and Mutation Landscape in 57 Pedigrees and Sporadic Cases. | Yu Y | Acta dermato-venereologica | 2021 | PMID: 34046686 |
Novel missense p.R252L mutation of ITGB4 compounded with known 3793+1G>A mutation associated with nonlethal epidermolysis bullosa-pyloric atresia with obstructive uropathy. | Ellis C | JAAD case reports | 2021 | PMID: 33937469 |
Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. | Varki R | Journal of medical genetics | 2006 | PMID: 16473856 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. | Nakano A | Pediatric research | 2001 | PMID: 11328943 |
Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. | Mellerio JE | The British journal of dermatology | 1998 | PMID: 9892956 |
Text-mined citations for rs147222357 ...
HelpRecord last updated Apr 06, 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.