dbSNP rs886060553: NIPBL:c.-416delC (chr5-36876834-TC-T) – 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.-416delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 79,382 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 0.00098 ( 0 hom., cov: 25)

Exomes 𝑓: 0.013 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

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 links:

NIPBL-DT (HGNC:51293): (NIPBL divergent transcript)

NIPBL-DT 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 afr. GnomAd4 allele frequency = 0.000984 (61/61990) while in subpopulation AFR AF = 0.0023 (38/16536). AF 95% confidence interval is 0.00172. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.-416delC		5_prime_UTR_variant	Exon 1 of 47	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13 link	c.-416delC		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8		Q6KC79-1

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

AN:

61936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000156

Gnomad ASJ

AF:

0.00132

Gnomad EAS

AF:

0.00146

Gnomad SAS

AF:

0.000726

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000575

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0128

AC:

223

AN:

17392

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

116

AN XY:

9008

show subpopulations

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

African (AFR)

AF:

0.0376

AC:

AN:

372

American (AMR)

AF:

0.0212

AC:

AN:

472

Ashkenazi Jewish (ASJ)

AF:

0.0313

AC:

AN:

448

East Asian (EAS)

AF:

0.0142

AC:

AN:

1764

South Asian (SAS)

AF:

0.00299

AC:

AN:

334

European-Finnish (FIN)

AF:

0.00306

AC:

AN:

1632

Middle Eastern (MID)

AF:

0.0256

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0121

AC:

136

AN:

11202

Other (OTH)

AF:

0.0147

AC:

AN:

1090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.327

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000984

AC:

AN:

61990

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

29532

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

16536

American (AMR)

AF:

0.000156

AC:

AN:

6420

Ashkenazi Jewish (ASJ)

AF:

0.00132

AC:

AN:

1512

East Asian (EAS)

AF:

0.00146

AC:

AN:

1372

South Asian (SAS)

AF:

0.000725

AC:

AN:

1380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

116

European-Non Finnish (NFE)

AF:

0.000575

AC:

AN:

29558

Other (OTH)

AF:

0.00

AC:

AN:

944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=281/19

polymorphism

(source)

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

Publications

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rs886060553

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over