chr5-37051759-AT-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_133433.4(NIPBL):c.6955-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,117,266 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.023 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.231

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 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 -16 ACMG points.

BP6

Variant 5-37051759-AT-A is Benign according to our data. Variant chr5-37051759-AT-A is described in ClinVar as [Benign]. Clinvar id is 197446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00166 (248/148958) while in subpopulation AFR AF = 0.00508 (208/40930). AF 95% confidence interval is 0.00452. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.6955-9delT		intron_variant	Intron 40 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.6955-9delT	intron_variant	Intron 40 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.6955-9delT	intron_variant	Intron 40 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000514335.1 link	n.828delT	non_coding_transcript_exon_variant	Exon 1 of 7	2
NIPBL	ENST00000652901.1 link	c.6955-9delT	intron_variant	Intron 40 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

249

AN:

148868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00512

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00108

Gnomad ASJ

AF:

0.000292

Gnomad EAS

AF:

0.000782

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.000409

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00147

GnomAD2 exomes

AF:

0.0162

AC:

2031

AN:

125324

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.0254

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.0151

Gnomad FIN exome

AF:

0.00509

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0232

AC:

22468

AN:

968308

Hom.:

Cov.:

AF XY:

0.0220

AC XY:

10602

AN XY:

482738

show subpopulations

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

African (AFR)

AF:

0.0297

AC:

653

AN:

21990

American (AMR)

AF:

0.0153

AC:

453

AN:

29576

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

296

AN:

16128

East Asian (EAS)

AF:

0.0115

AC:

283

AN:

24696

South Asian (SAS)

AF:

0.0174

AC:

977

AN:

56156

European-Finnish (FIN)

AF:

0.00594

AC:

226

AN:

38060

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

4282

European-Non Finnish (NFE)

AF:

0.0252

AC:

18641

AN:

738316

Other (OTH)

AF:

0.0224

AC:

875

AN:

39104

⚠️ 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: 0.252

Heterozygous variant carriers

3243

6487

9730

12974

16217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00166

AC:

248

AN:

148958

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

135

AN XY:

72606

show subpopulations

African (AFR)

AF:

0.00508

AC:

208

AN:

40930

American (AMR)

AF:

0.00108

AC:

AN:

14868

Ashkenazi Jewish (ASJ)

AF:

0.000292

AC:

AN:

3430

East Asian (EAS)

AF:

0.000784

AC:

AN:

5100

South Asian (SAS)

AF:

0.000213

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.000409

AC:

AN:

9768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

66904

Other (OTH)

AF:

0.00146

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0432

Hom.:

Asia WGS

AF:

0.0150

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Benign:2

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.23

La Branchor

0.34

BranchPoint Hunter

4.0

Mutation Taster

=100/0

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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chr5-37051759-AT-A

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