rs80358368

chr5-37060945-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_133433.4(NIPBL):c.7789del(p.Leu2597CysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F2596F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.54

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]

ACMG classification

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 5-37060945-TC-T is Pathogenic according to our data. Variant chr5-37060945-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 99942.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.7789del	p.Leu2597CysfsTer14	frameshift_variant	45/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.7789del	p.Leu2597CysfsTer14	frameshift_variant	45/47	1	NM_133433.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

NIPBL-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The NIPBL c.7789delC variant is predicted to result in a frameshift and premature protein termination (p.Leu2597Cysfs*14). This variant has been reported in an individual with Cornelia de Lange syndrome (Figure 1a, Ansari et al. 2014. PubMed ID: 25125236). It has also been reported de novo in a fetus with intrauterine growth restriction (Table S3, Fu et al. 2022. PubMed ID: 36307859). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in NIPBL are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 2016

The c.7789delC pathogenic variant in the NIPBL gene has been reported previously (as L2597Cfs*14 due to the use of alternative nomenclature) in association with Cornelia de Lange syndrome (Ansari et al., 2014). The c.7789delC variant causes a frameshift starting with codon Leucine 2597, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Leu2597CysfsX14. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.7789delC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.7789delC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs80358368; hg19: chr5-37061047;