Genetic Variant NIPBL:c.-428G>A (chr5-36876830-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133433.4(NIPBL):c.-428G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NIPBL
NM_133433.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.-428G>A		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.-428G>A		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8		Q6KC79-1

Frequencies

GnomAD3 genomes

AF:

0.0000443

AC:

AN:

67678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000564

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000505

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000312

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

145340

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3760

American (AMR)

AF:

0.000240

AC:

AN:

4168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5012

East Asian (EAS)

AF:

0.00

AC:

AN:

13736

South Asian (SAS)

AF:

0.00

AC:

AN:

2066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

748

European-Non Finnish (NFE)

AF:

0.0000220

AC:

AN:

91068

Other (OTH)

AF:

0.00

AC:

AN:

9252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000443

AC:

AN:

67678

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

32408

show subpopulations

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

African (AFR)

AF:

0.0000564

AC:

AN:

17734

American (AMR)

AF:

0.00

AC:

AN:

6684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1644

East Asian (EAS)

AF:

0.00

AC:

AN:

1916

South Asian (SAS)

AF:

0.000505

AC:

AN:

1982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.0000312

AC:

AN:

32028

Other (OTH)

AF:

0.00

AC:

AN:

982

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.033899), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

1.1

PromoterAI

0.0096

Neutral

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr5-36876830-G-A

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