Genetic Variant NIPBL:c.-429dupC (chr5-36876823-T-TC) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_133433.4(NIPBL):c.-429dupC variant causes a 5 prime UTR 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 0.00093 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NIPBL
NM_133433.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.51

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: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000131 (3/229684) while in subpopulation EAS AF = 0.000141 (3/21280). AF 95% confidence interval is 0.0000383. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.-429dupC		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.-429dupC		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8		Q6KC79-1

Frequencies

GnomAD3 genomes

AF:

0.000932

AC:

115

AN:

123356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000961

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000869

Gnomad ASJ

AF:

0.00100

Gnomad EAS

AF:

0.00123

Gnomad SAS

AF:

0.000269

Gnomad FIN

AF:

0.000122

Gnomad MID

AF:

0.00373

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00184

GnomAD4 exome

AF:

0.0000131

AC:

AN:

229684

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

117056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6458

American (AMR)

AF:

0.00

AC:

AN:

6848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8296

East Asian (EAS)

AF:

0.000141

AC:

AN:

21280

South Asian (SAS)

AF:

0.00

AC:

AN:

2884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1186

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

147294

Other (OTH)

AF:

0.00

AC:

AN:

15040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000932

AC:

115

AN:

123422

Hom.:

Cov.:

AF XY:

0.000904

AC XY:

AN XY:

59724

show subpopulations

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

African (AFR)

AF:

0.000959

AC:

AN:

32340

American (AMR)

AF:

0.000869

AC:

AN:

12664

Ashkenazi Jewish (ASJ)

AF:

0.00100

AC:

AN:

2998

East Asian (EAS)

AF:

0.00123

AC:

AN:

4058

South Asian (SAS)

AF:

0.000270

AC:

AN:

3708

European-Finnish (FIN)

AF:

0.000122

AC:

AN:

8166

Middle Eastern (MID)

AF:

0.00403

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

56914

Other (OTH)

AF:

0.00182

AC:

AN:

1652

⚠️ 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: 0.362

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000184

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=295/5

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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5-36876823-TC-TCC

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