5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr5-36952018-C-CTGTGTGTGTGTGTGTG
• rs60067315
• NM_133433.4:c.-79-1579_-79-1564dupTGTGTGTGTGTGTGTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_133433.4(NIPBL):​c.-79-1579_-79-1564dupTGTGTGTGTGTGTGTG 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. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.0065 (5 hom., cov: 0)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 5-36952018-C-CTGTGTGTGTGTGTGTG is Benign according to our data. Variant chr5-36952018-C-CTGTGTGTGTGTGTGTG is described in ClinVar as Benign. ClinVar VariationId is 2655411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00647 (659/101822) while in subpopulation EAS AF = 0.0128 (33/2576). AF 95% confidence interval is 0.0103. There are 5 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 659 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.-79-1579_-79-1564dupTGTGTGTGTGTGTGTG		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.-79-1579_-79-1564dupTGTGTGTGTGTGTGTG		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.-79-1579_-79-1564dupTGTGTGTGTGTGTGTG		intron	N/A	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.-79-1600_-79-1599insTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 659 AN: 101800 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00917

Gnomad AMR AF: 0.00794

Gnomad ASJ AF: 0.00257

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.00527

Gnomad FIN AF: 0.000469

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00154

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

GnomAD4 genome AF: 0.00647 AC: 659 AN: 101822 Hom.: 5 Cov.: 0 AF XY: 0.00652 AC XY: 311 AN XY: 47686

African (AFR) AF: 0.0114 AC: 284 AN: 24890

American (AMR) AF: 0.00793 AC: 83 AN: 10466

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 7 AN: 2728

East Asian (EAS) AF: 0.0128 AC: 33 AN: 2576

South Asian (SAS) AF: 0.00529 AC: 11 AN: 2078

European-Finnish (FIN) AF: 0.000469 AC: 2 AN: 4264

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

European-Non Finnish (NFE) AF: 0.00438 AC: 231 AN: 52700

Other (OTH) AF: 0.00153 AC: 2 AN: 1304

Alfa AF: 0.00 Hom.: 29

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;