5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr5-36952018-C-CTGTGTGTGTGTGTGTGTGTGTG
• rs60067315
• NM_133433.4:c.-79-1585_-79-1564dupTGTGTGTGTGTGTGTGTGTGTG

Variant summary

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

The NM_133433.4(NIPBL):​c.-79-1585_-79-1564dupTGTGTGTGTGTGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00026 (0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-79-1585_-79-1564dupTGTGTGTGTGTGTGTGTGTGTG		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_-79-1599insTGTGTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.000255 AC: 26 AN: 101920 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.000367

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000479

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000569

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000255 AC: 26 AN: 101942 Hom.: 0 Cov.: 0 AF XY: 0.000314 AC XY: 15 AN XY: 47734

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

African (AFR) AF: 0.000762 AC: 19 AN: 24938

American (AMR) AF: 0.0000955 AC: 1 AN: 10476

Ashkenazi Jewish (ASJ) AF: 0.000367 AC: 1 AN: 2728

East Asian (EAS) AF: 0.000387 AC: 1 AN: 2586

South Asian (SAS) AF: 0.000481 AC: 1 AN: 2080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.0000569 AC: 3 AN: 52746

Other (OTH) AF: 0.00 AC: 0 AN: 1304

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000168), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33

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;