chr5-36876801-GA-AT

Position:

• chr5-36876801-GA-AT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_133433.4(NIPBL):​c.-457_-456delGAinsAT variant causes a 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.32

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-36876801-GA-AT is Pathogenic according to our data. Variant chr5-36876801-GA-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1300231.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-457_-456delGAinsAT		5_prime_UTR_variant	1/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516	c.-457_-456delGAinsAT		5_prime_UTR_variant	1/47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238	c.-457_-456delGAinsAT		5_prime_UTR_variant	1/46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-457_-456delGAinsAT		upstream_gene_variant				ENSP00000499536.1

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: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental abnormality Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Oct 22, 2021

The variant c.-457_-456delinsAT was a de novo mutation introducing a novel ATG codon sequence in the 5’UTR of NIPBL, predicted to introduce uORF. The patient is a 15-year-old male with classic Cornelia de Lange syndrome. The reporter assay showed a significant decrease of GFP levels, with similar levels of mRNA as compared to wt constructs. Assessment of LCL in this patient showed consistent results with decreased NIPBL protein and unchanged mRNA levels. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-36876903;