Genetic Variant NIPBL:c.5863-20_5863-11delATATATATAT (chr5-37036347-GTATATATATA-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_133433.4(NIPBL):c.5863-20_5863-11delATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 384,512 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000074 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.30

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000201 (5/248482) while in subpopulation NFE AF = 0.0000279 (5/179290). AF 95% confidence interval is 0.0000102. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.5863-20_5863-11delATATATATAT		intron_variant	Intron 32 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.5863-31_5863-22delTATATATATA	intron_variant	Intron 32 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.5863-31_5863-22delTATATATATA	intron_variant	Intron 32 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.5863-31_5863-22delTATATATATA	intron_variant	Intron 32 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.00000735

AC:

AN:

136030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000201

AC:

AN:

248482

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

4370

American (AMR)

AF:

0.00

AC:

AN:

5214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6686

East Asian (EAS)

AF:

0.00

AC:

AN:

9774

South Asian (SAS)

AF:

0.00

AC:

AN:

10282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

864

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

179290

Other (OTH)

AF:

0.00

AC:

AN:

10974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000735

AC:

AN:

136030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65264

show subpopulations

African (AFR)

AF:

0.0000272

AC:

AN:

36784

American (AMR)

AF:

0.00

AC:

AN:

13328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3314

East Asian (EAS)

AF:

0.00

AC:

AN:

4744

South Asian (SAS)

AF:

0.00

AC:

AN:

4310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63874

Other (OTH)

AF:

0.00

AC:

AN:

1832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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