5-36876936-GC-G

Variant names:

• chr5-36876936-GC-G
• NM_133433.4:c.-315delC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133433.4(NIPBL):​c.-315delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 232,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• 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-DT (HGNC:51293): (NIPBL divergent transcript)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-315delC		5_prime_UTR_variant	Exon 1 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.-315delC		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-315delC		5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-315delC		5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1
NIPBL-DT	ENST00000649921.1	n.-237delG		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000129 AC: 3 AN: 232864 Hom.: 0 Cov.: 0 AF XY: 0.0000169 AC XY: 2 AN XY: 118526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6544

American (AMR) AF: 0.00 AC: 0 AN: 6992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8516

East Asian (EAS) AF: 0.00 AC: 0 AN: 21886

South Asian (SAS) AF: 0.00 AC: 0 AN: 2894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20542

Middle Eastern (MID) AF: 0.000818 AC: 1 AN: 1222

European-Non Finnish (NFE) AF: 0.0000134 AC: 2 AN: 148934

Other (OTH) AF: 0.00 AC: 0 AN: 15334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Uncertain:1

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the NIPBL gene. It does not change the encoded amino acid sequence of the NIPBL protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NIPBL-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=247/53	polymorphism

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

Other links and lift over

hg19: chr5-36877038;