rs3822471

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.2021A>G(p.Asn674Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,756 control chromosomes in the GnomAD database, including 12,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N674H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1225 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10863 hom. )

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.597

Publications

28 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 (MetaRNN=0.0011794567).

BP6

Variant 5-36985201-A-G is Benign according to our data. Variant chr5-36985201-A-G is described in ClinVar as Benign. ClinVar VariationId is 96333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.2021A>G	p.Asn674Ser	missense_variant	Exon 10 of 47	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPBL	ENST00000282516.13 link	c.2021A>G	p.Asn674Ser	missense_variant	Exon 10 of 47	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.2021A>G	p.Asn674Ser	missense_variant	Exon 10 of 46	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.2021A>G	p.Asn674Ser	missense_variant	Exon 10 of 46			ENSP00000499536.1	A0A590UJS4
NIPBL	ENST00000504430.5 link	n.1641A>G		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

18554

AN:

151998

Hom.:

1222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0980

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.137

AC:

34363

AN:

250244

AF XY:

0.133

show subpopulations

Gnomad AFR exome

AF:

0.0923

Gnomad AMR exome

AF:

0.234

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.118

AC:

172650

AN:

1461640

Hom.:

10863

Cov.:

AF XY:

0.118

AC XY:

85718

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.0979

AC:

3275

AN:

33458

American (AMR)

AF:

0.227

AC:

10142

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

5444

AN:

26130

East Asian (EAS)

AF:

0.101

AC:

4019

AN:

39694

South Asian (SAS)

AF:

0.109

AC:

9378

AN:

86252

European-Finnish (FIN)

AF:

0.127

AC:

6786

AN:

53392

Middle Eastern (MID)

AF:

0.166

AC:

957

AN:

5768

European-Non Finnish (NFE)

AF:

0.112

AC:

124907

AN:

1111928

Other (OTH)

AF:

0.128

AC:

7742

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

9521

19042

28563

38084

47605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4614

9228

13842

18456

23070

<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:

0.122

AC:

18580

AN:

152116

Hom.:

1225

Cov.:

AF XY:

0.125

AC XY:

9301

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0980

AC:

4068

AN:

41510

American (AMR)

AF:

0.189

AC:

2882

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

703

AN:

3468

East Asian (EAS)

AF:

0.127

AC:

660

AN:

5180

South Asian (SAS)

AF:

0.118

AC:

567

AN:

4818

European-Finnish (FIN)

AF:

0.132

AC:

1402

AN:

10592

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7884

AN:

67988

Other (OTH)

AF:

0.153

AC:

323

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

857

1714

2570

3427

4284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.122

Hom.:

5495

Bravo

AF:

0.126

TwinsUK

AF:

0.107

AC:

398

ALSPAC

AF:

0.102

AC:

394

ESP6500AA

AF:

0.0921

AC:

406

ESP6500EA

AF:

0.125

AC:

1074

ExAC

AF:

0.131

AC:

15954

Asia WGS

AF:

0.169

AC:

585

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.129

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Jan 13, 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 11, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

5.8

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

PhyloP100

0.60

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.23

Sift

Benign

0.18

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0

B;B

Vest4

0.031

MPC

0.15

ClinPred

0.0018

GERP RS

2.3

Varity_R

0.026

gMVP

0.21

Mutation Taster

=98/2

polymorphism (auto)

(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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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