NM_133433.4:c.4561-9T>A

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.4561-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,574,622 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 82 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 96 hom. )

Consequence

NIPBL
NM_133433.4 intron

Scores

Splicing: ADA: 0.003446

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.47

Publications

2 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=-0.77).

BP6

Variant 5-37014674-T-A is Benign according to our data. Variant chr5-37014674-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NIPBL	NM_133433.4	MANE Select	c.4561-9T>A	intron	N/A	NP_597677.2
NIPBL	NM_001438586.1		c.4561-9T>A	intron	N/A	NP_001425515.1
NIPBL	NM_015384.5		c.4561-9T>A	intron	N/A	NP_056199.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.4561-9T>A	intron	N/A	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2	TSL:1	c.4561-9T>A	intron	N/A	ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1		c.4561-9T>A	intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3024

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0622

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00334

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00798

AC:

1997

AN:

250332

AF XY:

0.00733

show subpopulations

Gnomad AFR exome

AF:

0.0659

Gnomad AMR exome

AF:

0.00541

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00397

Gnomad OTH exome

AF:

0.00590

GnomAD4 exome

AF:

0.00498

AC:

7086

AN:

1422322

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

3626

AN XY:

710158

show subpopulations

African (AFR)

AF:

0.0671

AC:

2189

AN:

32624

American (AMR)

AF:

0.00584

AC:

260

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.000425

AC:

AN:

25860

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39392

South Asian (SAS)

AF:

0.00922

AC:

784

AN:

85070

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.0224

AC:

127

AN:

5676

European-Non Finnish (NFE)

AF:

0.00303

AC:

3260

AN:

1076704

Other (OTH)

AF:

0.00757

AC:

447

AN:

59080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

310

620

929

1239

1549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.0199

AC:

3028

AN:

152300

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1451

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0621

AC:

2580

AN:

41552

American (AMR)

AF:

0.00863

AC:

132

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00911

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00334

AC:

227

AN:

68016

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

145

289

434

578

723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00767

Hom.:

Bravo

AF:

0.0231

Asia WGS

AF:

0.00377

AC:

AN:

3466

EpiCase

AF:

0.00382

EpiControl

AF:

0.00640

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Cornelia de Lange syndrome 1 (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.49

PhyloP100

2.5

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0034

dbscSNV1_RF

Benign

0.096

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over