5-37036347-GTATATATATATA-GTATATATATATATA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_133433.4(NIPBL):c.5863-12_5863-11dupAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0079 ( 6 hom., cov: 0)

Exomes 𝑓: 0.026 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0120

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 5-37036347-G-GTA is Benign according to our data. Variant chr5-37036347-G-GTA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96347.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00793 (1079/135980) while in subpopulation SAS AF = 0.0175 (75/4284). AF 95% confidence interval is 0.0143. There are 6 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 1079 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.5863-12_5863-11dupAT		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.5863-32_5863-31insTA	intron_variant	Intron 32 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.5863-32_5863-31insTA	intron_variant	Intron 32 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.5863-32_5863-31insTA	intron_variant	Intron 32 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.00793

AC:

1079

AN:

135986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00579

Gnomad AMR

AF:

0.00390

Gnomad ASJ

AF:

0.00302

Gnomad EAS

AF:

0.0169

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00345

Gnomad NFE

AF:

0.00655

Gnomad OTH

AF:

0.00655

GnomAD2 exomes

AF:

0.0307

AC:

1011

AN:

32888

AF XY:

0.0341

show subpopulations

Gnomad AFR exome

AF:

0.00654

Gnomad AMR exome

AF:

0.0192

Gnomad ASJ exome

AF:

0.0238

Gnomad EAS exome

AF:

0.0288

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0359

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0263

AC:

6378

AN:

242628

Hom.:

Cov.:

AF XY:

0.0278

AC XY:

3686

AN XY:

132528

show subpopulations

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

African (AFR)

AF:

0.0183

AC:

AN:

4322

American (AMR)

AF:

0.0171

AC:

AN:

5140

Ashkenazi Jewish (ASJ)

AF:

0.0226

AC:

148

AN:

6546

East Asian (EAS)

AF:

0.0270

AC:

259

AN:

9578

South Asian (SAS)

AF:

0.0369

AC:

372

AN:

10074

European-Finnish (FIN)

AF:

0.0137

AC:

275

AN:

20022

Middle Eastern (MID)

AF:

0.0164

AC:

AN:

854

European-Non Finnish (NFE)

AF:

0.0277

AC:

4851

AN:

175286

Other (OTH)

AF:

0.0270

AC:

292

AN:

10806

⚠️ 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: 0.305

Heterozygous variant carriers

480

961

1441

1922

2402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

228

342

456

570

<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:

0.00793

AC:

1079

AN:

135980

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

498

AN XY:

65258

show subpopulations

African (AFR)

AF:

0.0112

AC:

414

AN:

36828

American (AMR)

AF:

0.00390

AC:

AN:

13334

Ashkenazi Jewish (ASJ)

AF:

0.00302

AC:

AN:

3312

East Asian (EAS)

AF:

0.0169

AC:

AN:

4724

South Asian (SAS)

AF:

0.0175

AC:

AN:

4284

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

6686

Middle Eastern (MID)

AF:

0.00370

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.00655

AC:

418

AN:

63834

Other (OTH)

AF:

0.00651

AC:

AN:

1844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00366

Hom.:

457

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 15, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 19, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.012

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over