rs587783968
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_133433.4(NIPBL):c.5329-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
NIPBL
NM_133433.4 intron
NM_133433.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.324
Genes affected
NIPBL (HGNC:28862): (NIPBL cohesin loading factor) This gene encodes the homolog of the Drosophila melanogaster Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins. The Drosophila protein facilitates enhancer-promoter communication of remote enhancers and plays a role in developmental regulation. It is also homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. The human protein has a bipartite nuclear targeting sequence and a putative HEAT repeat. Condensins, cohesins and other complexes with chromosome-related functions also contain HEAT repeats. Mutations in this gene result in Cornelia de Lange syndrome, a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and cognitive disability. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-37022036-A-G is Pathogenic according to our data. Variant chr5-37022036-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 159142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37022036-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NIPBL | ENST00000282516.13 | c.5329-15A>G | intron_variant | Intron 27 of 46 | 1 | NM_133433.4 | ENSP00000282516.8 | |||
| NIPBL | ENST00000448238.2 | c.5329-15A>G | intron_variant | Intron 27 of 45 | 1 | ENSP00000406266.2 | ||||
| NIPBL | ENST00000652901.1 | c.5329-15A>G | intron_variant | Intron 27 of 45 | ENSP00000499536.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455414Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 724434
GnomAD4 exome
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29
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1
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Jun 25, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 20, 2023 | 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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 159142). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Sep 01, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 11, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cornelia de Lange syndrome 1 (MIM#122470). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0217 - Non-coding variant with known effect. RNA studies have shown this variant results in in-frame skipping of exon 28 (PMID: 26925417). (SP) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in an individual with Cornelia de Lange syndrome 1 in the literature (PMID: 26925417). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | NIPBL: PM6:Strong, PVS1:Strong, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 30, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2022 | 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) - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2022 | 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. - |
NIPBL-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 13, 2022 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 15
Find out detailed SpliceAI scores and Pangolin per-transcript scores at