ClinVar Genomic variation as it relates to human health
NM_133433.4(NIPBL):c.5329-15A>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_133433.4(NIPBL):c.5329-15A>G
Variation ID: 159142 Accession: VCV000159142.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p13.2 5: 37022036 (GRCh38) [ NCBI UCSC ] 5: 37022138 (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 Nov 23, 2014 May 1, 2024 Jul 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_133433.4:c.5329-15A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_015384.5:c.5329-15A>G intron variant NC_000005.10:g.37022036A>G NC_000005.9:g.37022138A>G NG_006987.2:g.150154A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000005.10:37022035: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
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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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NIPBL | Sufficient evidence for dosage pathogenicity | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
1748 | 1799 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2023 | RCV000795862.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2022 | RCV001582611.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 19, 2022 | RCV002515967.2 | |
NIPBL-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2022 | RCV003415975.4 |
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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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002054153.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Oct 30, 2020)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV000193941.3
First in ClinVar: Nov 23, 2014 Last updated: Jan 29, 2022 |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517798.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573294.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26925417). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26925417). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 26925417). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000159142). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Chronic diarrhea (present) , Short stature (present) , Neonatal hyperbilirubinemia (present) , Failure to thrive (present) , Normocytic anemia (present) , Normochromic anemia (present)
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Pathogenic
(Oct 19, 2022)
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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: SCV001819552.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that c.5329-15A>G results in in-frame skipping of exon 28 and has a damaging effect on the gene product (Nizon et al., … (more)
Published functional studies demonstrate that c.5329-15A>G results in in-frame skipping of exon 28 and has a damaging effect on the gene product (Nizon et al., 2016; Teresa-Rodrigo et al., 2016; Masciadri et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27164022, 26701315, 26925417, 30538663, 34717699, 35183220) (less)
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Pathogenic
(Dec 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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NIPBL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004113400.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NIPBL c.5329-15A>G variant is predicted to interfere with splicing. This variant has been previously reported in individuals with Cornelia de Lange syndrome or neurodevelopmental … (more)
The NIPBL c.5329-15A>G variant is predicted to interfere with splicing. This variant has been previously reported in individuals with Cornelia de Lange syndrome or neurodevelopmental disorders (Teresa-Rodrigo et al. 2016. PubMed ID: 26925417; Nizon et al. 2016. PubMed ID: 26701315; Table 3, Pablo et al. 2021. PubMed ID: 34717699; Álvarez-Mora et al. 2022. PubMed ID: 35183220). Functional studies have found that the presence of this variant results in the skipping of exon 28, with a shorter protein product which retains its reading frame (Teresa-Rodrigo et al. 2016. PubMed ID: 26925417). This variant has not been reported in a large polulation database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Jul 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000935340.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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: 159142). This variant has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 26701315, 26925417). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 27 of the NIPBL gene. It does not directly change the encoded amino acid sequence of the NIPBL protein. (less)
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Pathogenic
(Sep 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003536981.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.5329-15A>G intronic alteration consists of an A to G substitution 15 nucleotides before exon 28 (coding exon 27) of the NIPBL gene. This variant … (more)
The c.5329-15A>G intronic alteration consists of an A to G substitution 15 nucleotides before exon 28 (coding exon 27) of the NIPBL gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with Cornelia de Lange syndrome (Nizon, 2016; Teresa-Rodrigo, 2016). This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing (Nizon, 2016; Teresa-Rodrigo, 2016). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jun 25, 2019)
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no assertion criteria provided
Method: clinical testing
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Cornelia de Lange syndrome 1
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001192590.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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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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Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome. | Teresa-Rodrigo ME | BioMed research international | 2016 | PMID: 26925417 |
A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome. | Nizon M | Clinical genetics | 2016 | PMID: 26701315 |
Text-mined citations for rs587783968 ...
HelpRecord last updated May 19, 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.