Genetic Variant NIPBL:c.-79-1587_-79-1564dupTGTGTGTGTGTGTGTGTGTGTGTG (chr5-36952018-C-CTGTGTGTGTGTGTGTGTGTGTGTG) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_133433.4(NIPBL):c.-79-1587_-79-1564dupTGTGTGTGTGTGTGTGTGTGTGTG 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 0.000059 ( 0 hom., cov: 0)

Consequence

NIPBL
NM_133433.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.326

Publications

0 publications found

Variant links:

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

NIPBL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.-79-1587_-79-1564dupTGTGTGTGTGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 46	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPBL	ENST00000282516.13 link	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTGTGTGTG	intron_variant	Intron 1 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTGTGTGTG	intron_variant	Intron 1 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.-79-1600_-79-1599insTGTGTGTGTGTGTGTGTGTGTGTG	intron_variant	Intron 1 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.0000589

AC:

AN:

101926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000955

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

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

GnomAD4 genome

AF:

0.0000589

AC:

AN:

101926

Hom.:

Cov.:

AF XY:

0.0000419

AC XY:

AN XY:

47712

show subpopulations

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

African (AFR)

AF:

0.000201

AC:

AN:

24902

American (AMR)

AF:

0.0000955

AC:

AN:

10468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2728

East Asian (EAS)

AF:

0.00

AC:

AN:

2592

South Asian (SAS)

AF:

0.00

AC:

AN:

2088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52752

Other (OTH)

AF:

0.00

AC:

AN:

1296

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Publications

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5-36952018-CTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over