chr5-37008730-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_133433.4(NIPBL):c.4421+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 1,431,466 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 83 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 87 hom. )

Consequence

NIPBL
NM_133433.4 splice_region, intron

Scores

Splicing: ADA: 0.0001526

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.655

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 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 5-37008730-A-G is Benign according to our data. Variant chr5-37008730-A-G is described in ClinVar as [Benign]. Clinvar id is 96341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.4421+7A>G		splice_region_variant, intron_variant	Intron 20 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.4421+7A>G	splice_region_variant, intron_variant	Intron 20 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.4421+7A>G	splice_region_variant, intron_variant	Intron 20 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.4421+7A>G	splice_region_variant, intron_variant	Intron 20 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3034

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0623

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00953

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.00791

AC:

1978

AN:

249976

AF XY:

0.00739

show subpopulations

Gnomad AFR exome

AF:

0.0666

Gnomad AMR exome

AF:

0.00550

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00399

Gnomad OTH exome

AF:

0.00560

GnomAD4 exome

AF:

0.00511

AC:

6541

AN:

1279164

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

3359

AN XY:

646180

show subpopulations

African (AFR)

AF:

0.0666

AC:

1984

AN:

29794

American (AMR)

AF:

0.00587

AC:

261

AN:

44476

Ashkenazi Jewish (ASJ)

AF:

0.000440

AC:

AN:

24982

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38694

South Asian (SAS)

AF:

0.00933

AC:

770

AN:

82534

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.0220

AC:

119

AN:

5404

European-Non Finnish (NFE)

AF:

0.00313

AC:

2964

AN:

945746

Other (OTH)

AF:

0.00782

AC:

424

AN:

54192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

313

627

940

1254

1567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0199

AC:

3038

AN:

152302

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1452

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0622

AC:

2586

AN:

41556

American (AMR)

AF:

0.00857

AC:

131

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00933

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00337

AC:

229

AN:

68030

Other (OTH)

AF:

0.0165

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

138

276

414

552

690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.0231

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.00387

EpiControl

AF:

0.00664

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Nov 01, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

Apr 18, 2015

GeneDx

Significance: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. -

Jan 23, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cornelia de Lange syndrome 1

Benign:4

Feb 03, 2025

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

- -

Mar 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

9.6

(source)

DANN

Benign

0.73

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.010

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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chr5-37008730-A-G

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