5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTG

Variant names:

• chr5-36952018-CTGTG-C
• rs60067315
• NM_133433.4:c.-79-1567_-79-1564delTGTG

Variant summary

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

The NM_133433.4(NIPBL):​c.-79-1567_-79-1564delTGTG 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 0.0011 (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 eas. GnomAd4 allele frequency = 0.00108 (110/101954) while in subpopulation EAS AF = 0.00619 (16/2586). AF 95% confidence interval is 0.00388. There are 1 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-79-1567_-79-1564delTGTG		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.-79-1599_-79-1596delTGTG		intron_variant	Intron 1 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-79-1599_-79-1596delTGTG		intron_variant	Intron 1 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-79-1599_-79-1596delTGTG		intron_variant	Intron 1 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 111 AN: 101932 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0320

Gnomad AMR AF: 0.000764

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00617

Gnomad SAS AF: 0.00144

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000436

Gnomad OTH AF: 0.000772

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

GnomAD4 genome AF: 0.00108 AC: 110 AN: 101954 Hom.: 1 Cov.: 0 AF XY: 0.00115 AC XY: 55 AN XY: 47746

African (AFR) AF: 0.00156 AC: 39 AN: 24944

American (AMR) AF: 0.000764 AC: 8 AN: 10478

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

East Asian (EAS) AF: 0.00619 AC: 16 AN: 2586

South Asian (SAS) AF: 0.000962 AC: 2 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: 0.000436 AC: 23 AN: 52748

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

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

dbSNP: rs60067315; hg19: chr5-36952120;