5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr5-36952018-C-CTG
• rs60067315
• NM_133433.4:c.-79-1565_-79-1564dupTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_133433.4(NIPBL):​c.-79-1565_-79-1564dupTG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.059 (241 hom., cov: 0)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-79-1565_-79-1564dupTG		intron_variant	Intron 1 of 46	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.-79-1600_-79-1599insTG		intron_variant	Intron 1 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-79-1600_-79-1599insTG		intron_variant	Intron 1 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-79-1600_-79-1599insTG		intron_variant	Intron 1 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 5956 AN: 101800 Hom.: 241 Cov.: 0

Gnomad AFR AF: 0.0944

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0562

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0580

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0585 AC: 5958 AN: 101820 Hom.: 241 Cov.: 0 AF XY: 0.0586 AC XY: 2795 AN XY: 47682

African (AFR) AF: 0.0944 AC: 2351 AN: 24906

American (AMR) AF: 0.0412 AC: 432 AN: 10476

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 179 AN: 2726

East Asian (EAS) AF: 0.0116 AC: 30 AN: 2586

South Asian (SAS) AF: 0.0758 AC: 157 AN: 2070

European-Finnish (FIN) AF: 0.0291 AC: 124 AN: 4258

Middle Eastern (MID) AF: 0.0556 AC: 9 AN: 162

European-Non Finnish (NFE) AF: 0.0476 AC: 2510 AN: 52684

Other (OTH) AF: 0.0585 AC: 76 AN: 1300

Alfa AF: 0.0208 Hom.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs60067315; hg19: chr5-36952120;