rs587784019

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_133433.4(NIPBL):​c.6632_6634delAAG​(p.Glu2211del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NIPBL
NM_133433.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.57
Variant links:
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_133433.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 5-37048540-CAAG-C is Pathogenic according to our data. Variant chr5-37048540-CAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159204.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NIPBLNM_133433.4 linkc.6632_6634delAAG p.Glu2211del disruptive_inframe_deletion Exon 39 of 47 ENST00000282516.13 NP_597677.2 Q6KC79-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NIPBLENST00000282516.13 linkc.6632_6634delAAG p.Glu2211del disruptive_inframe_deletion Exon 39 of 47 1 NM_133433.4 ENSP00000282516.8 Q6KC79-1
NIPBLENST00000448238.2 linkc.6632_6634delAAG p.Glu2211del disruptive_inframe_deletion Exon 39 of 46 1 ENSP00000406266.2 Q6KC79-2
NIPBLENST00000652901.1 linkc.6632_6634delAAG p.Glu2211del disruptive_inframe_deletion Exon 39 of 46 ENSP00000499536.1 A0A590UJS4

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:1
Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587784019; hg19: chr5-37048642; API