5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr5-36952018-C-CTGTGTGTGTGTGTG
• rs60067315
• NM_133433.4:c.-79-1577_-79-1564dupTGTGTGTGTGTGTG

Variant summary

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

The NM_133433.4(NIPBL):​c.-79-1577_-79-1564dupTGTGTGTGTGTGTG 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 0.019 (35 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 eas. GnomAd4 allele frequency = 0.0186 (1890/101674) while in subpopulation EAS AF = 0.0372 (96/2578). AF 95% confidence interval is 0.0312. There are 35 homozygotes in GnomAd4. There are 897 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1890 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-79-1577_-79-1564dupTGTGTGTGTGTGTG		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_-79-1599insTGTGTGTGTGTGTG		intron_variant	Intron 1 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-79-1600_-79-1599insTGTGTGTGTGTGTG		intron_variant	Intron 1 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-79-1600_-79-1599insTGTGTGTGTGTGTG		intron_variant	Intron 1 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 1890 AN: 101652 Hom.: 35 Cov.: 0

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0129

Gnomad EAS AF: 0.0372

Gnomad SAS AF: 0.00864

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0112

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0201

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

GnomAD4 genome AF: 0.0186 AC: 1890 AN: 101674 Hom.: 35 Cov.: 0 AF XY: 0.0188 AC XY: 897 AN XY: 47606

African (AFR) AF: 0.0315 AC: 782 AN: 24838

American (AMR) AF: 0.0135 AC: 141 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 35 AN: 2722

East Asian (EAS) AF: 0.0372 AC: 96 AN: 2578

South Asian (SAS) AF: 0.00867 AC: 18 AN: 2076

European-Finnish (FIN) AF: 0.0127 AC: 54 AN: 4242

Middle Eastern (MID) AF: 0.0123 AC: 2 AN: 162

European-Non Finnish (NFE) AF: 0.0134 AC: 706 AN: 52648

Other (OTH) AF: 0.0200 AC: 26 AN: 1302

Alfa AF: 0.0114 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;