rs145778995

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_133433.4(NIPBL):c.6109-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,613,020 control chromosomes in the GnomAD database, including 35 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 31 hom. )

Consequence

NIPBL
NM_133433.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00006533

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0820

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 5-37044344-T-C is Benign according to our data. Variant chr5-37044344-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 96349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37044344-T-C is described in Lovd as [Likely_benign]. Variant chr5-37044344-T-C is described in Lovd as [Benign]. Variant chr5-37044344-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00362 (551/152324) while in subpopulation SAS AF= 0.00538 (26/4834). AF 95% confidence interval is 0.00483. There are 4 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 551 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4 linkuse as main transcript	c.6109-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13 linkuse as main transcript	c.6109-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_133433.4	P1	Q6KC79-1
NIPBL	ENST00000448238.2 linkuse as main transcript	c.6109-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1			Q6KC79-2
NIPBL	ENST00000652901.1 linkuse as main transcript	c.6109-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00362

AC:

551

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00537

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00528

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00413

AC:

1034

AN:

250088

Hom.:

AF XY:

0.00437

AC XY:

592

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00726

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00520

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00580

Gnomad OTH exome

AF:

0.00444

GnomAD4 exome

AF:

0.00564

AC:

8243

AN:

1460696

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

4194

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00678

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00538

Gnomad4 FIN exome

AF:

0.00236

Gnomad4 NFE exome

AF:

0.00635

Gnomad4 OTH exome

AF:

0.00489

GnomAD4 genome

AF:

0.00362

AC:

551

AN:

152324

Hom.:

Cov.:

AF XY:

0.00362

AC XY:

270

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00490

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00528

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00579

Hom.:

Bravo

AF:

0.00376

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NIPBL: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2019	This variant is associated with the following publications: (PMID: 17661813, 24038889, 24918291, 15318302) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 30, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

NIPBL-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

0.48

Dann

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000065

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over