NM_133433.4:c.6589+5G>A

Variant names:

• chr5-37046204-G-A
• rs1554032266
• NM_133433.4:c.6589+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_133433.4(NIPBL):​c.6589+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Scores: Splicing: ADA: 0.5395
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.118
• Publications: 0 publications found

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]

NIPBL Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-37046204-G-A is Pathogenic according to our data. Variant chr5-37046204-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476595.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6589+5G>A		splice_region_variant, intron_variant	Intron 38 of 46	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6589+5G>A		splice_region_variant, intron_variant	Intron 38 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6589+5G>A		splice_region_variant, intron_variant	Intron 38 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6589+5G>A		splice_region_variant, intron_variant	Intron 38 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:1

Jan 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in individuals affected with Cornelia de Lange Syndrome (PMID: 20824775, Invitae). In one of these individuals, it was reported to be de novo (PMID: 20824775). A different variant affecting this nucleotide (c.6589+5G>C) has been determined to be pathogenic (PMID: 22857006). This suggests that this nucleotide is critical for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this c.6589+5G>A variant may alter RNA splicing, although this prediction has not been confirmed by published studies. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 38 of the NIPBL gene. It does not directly change the encoded amino acid sequence of the NIPBL protein, but it affects a nucleotide within the consensus splice site of the intron. -

not provided Uncertain:1

Feb 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 25525159, 22857006, 20824775, 32856424) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.61
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.53
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

Other links and lift over

dbSNP: rs1554032266; hg19: chr5-37046306;