5-37036390-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_133433.4(NIPBL):c.5874C>T(p.Ser1958Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,272,910 control chromosomes in the GnomAD database, including 14,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1650 hom., cov: 27)

Exomes 𝑓: 0.14 ( 12996 hom. )

Consequence

NIPBL
NM_133433.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.66

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 5-37036390-C-T is Benign according to our data. Variant chr5-37036390-C-T is described in ClinVar as Benign. ClinVar VariationId is 96348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.5874C>T	p.Ser1958Ser	synonymous_variant	Exon 33 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NIPBL	ENST00000282516.13 link	c.5874C>T	p.Ser1958Ser	synonymous_variant	Exon 33 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2 link	c.5874C>T	p.Ser1958Ser	synonymous_variant	Exon 33 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1 link	c.5874C>T	p.Ser1958Ser	synonymous_variant	Exon 33 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

19486

AN:

141628

Hom.:

1653

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0544

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.170

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.151

GnomAD2 exomes

AF:

0.151

AC:

17008

AN:

112882

AF XY:

0.158

show subpopulations

Gnomad AFR exome

AF:

0.0371

Gnomad AMR exome

AF:

0.0906

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.256

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.144

AC:

163069

AN:

1131282

Hom.:

12996

Cov.:

AF XY:

0.148

AC XY:

82448

AN XY:

558642

show subpopulations

African (AFR)

AF:

0.0417

AC:

1024

AN:

24552

American (AMR)

AF:

0.0988

AC:

2127

AN:

21530

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

3445

AN:

19404

East Asian (EAS)

AF:

0.288

AC:

8025

AN:

27882

South Asian (SAS)

AF:

0.222

AC:

9953

AN:

44914

European-Finnish (FIN)

AF:

0.163

AC:

6287

AN:

38564

Middle Eastern (MID)

AF:

0.152

AC:

485

AN:

3188

European-Non Finnish (NFE)

AF:

0.138

AC:

125115

AN:

905980

Other (OTH)

AF:

0.146

AC:

6608

AN:

45268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

4988

9976

14964

19952

24940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4712

9424

14136

18848

23560

<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:

0.137

AC:

19473

AN:

141628

Hom.:

1650

Cov.:

AF XY:

0.142

AC XY:

9757

AN XY:

68470

show subpopulations

African (AFR)

AF:

0.0542

AC:

2057

AN:

37952

American (AMR)

AF:

0.127

AC:

1778

AN:

13960

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

657

AN:

3432

East Asian (EAS)

AF:

0.318

AC:

1566

AN:

4920

South Asian (SAS)

AF:

0.253

AC:

1155

AN:

4564

European-Finnish (FIN)

AF:

0.183

AC:

1384

AN:

7580

Middle Eastern (MID)

AF:

0.177

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.157

AC:

10389

AN:

66134

Other (OTH)

AF:

0.154

AC:

296

AN:

1926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

776

1551

2327

3102

3878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.138

Hom.:

807

Bravo

AF:

0.127

Asia WGS

AF:

0.247

AC:

843

AN:

3416

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Benign:4

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

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. -

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Jul 13, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 15, 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. -

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

-0.47

CADD

Benign

2.6

(source)

DANN

Benign

0.48

PhyloP100

-1.7

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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