rs587783968

Positions:

• chr5-37022036-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_133433.4(NIPBL):​c.5329-15A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.5329-15A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.5329-15A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_133433.4	ENSP00000282516	P1
NIPBL	ENST00000448238.2	c.5329-15A>G		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000406266
NIPBL	ENST00000652901.1	c.5329-15A>G		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499536

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455414 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724434

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:5

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	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	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	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 159142). 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. This variant is not present in population databases (gnomAD no frequency). 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. -

not provided Pathogenic:2

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 1
DS_AL_spliceai		0.54		Position offset: 15

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783968; hg19: chr5-37022138;