5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr5-36952018-C-CTGTGTGTGTGTGTGTGTG
• rs60067315
• NM_133433.4:c.-79-1581_-79-1564dupTGTGTGTGTGTGTGTGTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_133433.4(NIPBL):​c.-79-1581_-79-1564dupTGTGTGTGTGTGTGTGTG 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0012 (1 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (124/101904) while in subpopulation AFR AF = 0.00265 (66/24912). AF 95% confidence interval is 0.00214. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-79-1581_-79-1564dupTGTGTGTGTGTGTGTGTG		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_-79-1599insTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 124 AN: 101882 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000573

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000479

Gnomad FIN AF: 0.000704

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000796

Gnomad OTH AF: 0.000772

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

GnomAD4 genome AF: 0.00122 AC: 124 AN: 101904 Hom.: 1 Cov.: 0 AF XY: 0.00134 AC XY: 64 AN XY: 47716

African (AFR) AF: 0.00265 AC: 66 AN: 24912

American (AMR) AF: 0.000573 AC: 6 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2728

East Asian (EAS) AF: 0.00193 AC: 5 AN: 2586

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

European-Finnish (FIN) AF: 0.000704 AC: 3 AN: 4262

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

European-Non Finnish (NFE) AF: 0.000796 AC: 42 AN: 52742

Other (OTH) AF: 0.000767 AC: 1 AN: 1304

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;