rs1554017345
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_133433.4(NIPBL):c.2464_2467del(p.Gln822AsnfsTer24) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
NM_133433.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.33
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 5-36985640-TAAAC-T is Pathogenic according to our data. Variant chr5-36985640-TAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 436012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.2464_2467del | p.Gln822AsnfsTer24 | frameshift_variant | 10/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.2464_2467del | p.Gln822AsnfsTer24 | frameshift_variant | 10/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.2464_2467del | p.Gln822AsnfsTer24 | frameshift_variant | 10/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.2464_2467del | p.Gln822AsnfsTer24 | frameshift_variant | 10/46 | ||||
NIPBL | ENST00000504430.5 | n.2084_2087del | non_coding_transcript_exon_variant | 6/8 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
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 | Genetic Services Laboratory, University of Chicago | Feb 09, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NIPBL are known to be pathogenic (PMID: 15318302, 19763162, 23505322, 29995837). This variant has not been reported in the literature in individuals with NIPBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 436012). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln822Asnfs*24) in the NIPBL gene. It is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at