rs80358367
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_133433.4(NIPBL):c.133C>T(p.Arg45Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
NIPBL
NM_133433.4 stop_gained
NM_133433.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.03
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-36955540-C-T is Pathogenic according to our data. Variant chr5-36955540-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 99920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36955540-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.133C>T | p.Arg45Ter | stop_gained | 3/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.133C>T | p.Arg45Ter | stop_gained | 3/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.133C>T | p.Arg45Ter | stop_gained | 3/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.133C>T | p.Arg45Ter | stop_gained | 3/46 | ||||
NIPBL | ENST00000505998.5 | n.112C>T | non_coding_transcript_exon_variant | 2/8 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Arg45*) in the NIPBL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NIPBL are known to be pathogenic (PMID: 15318302, 19763162, 23505322, 29995837). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Cornelia de Lange syndrome (PMID: 20824775). ClinVar contains an entry for this variant (Variation ID: 99920). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2018 | The R45X nonsense variant in the NIPBL gene has been reported previously in association with Cornelia de Lange syndrome (Oliveira et al., 2010; Landrum et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R45X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, R45X is considered a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 15, 2015 | - - |
NIPBL-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 10, 2023 | The NIPBL c.133C>T variant is predicted to result in premature protein termination (p.Arg45*). This variant was reported in two individuals with Cornelia de Lange syndrome (Oliveira et al. 2010. PubMed ID: 20824775; Table S1, Levy et al. 2022. PubMed ID: 35904121). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in NIPBL are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at