5-37051759-A-AT

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_133433.4(NIPBL):c.6955-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00889 in 1,207,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.010 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.231

Publications

0 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 -9 ACMG points.

BP6

Variant 5-37051759-A-AT is Benign according to our data. Variant chr5-37051759-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1950511.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000181 (27/149054) while in subpopulation EAS AF = 0.000588 (3/5102). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.6955-9dupT		splice_region_variant, intron_variant	Intron 40 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.6955-9dupT	splice_region_variant, intron_variant	Intron 40 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.6955-9dupT	splice_region_variant, intron_variant	Intron 40 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000514335.1 link	n.828dupT	non_coding_transcript_exon_variant	Exon 1 of 7	2
NIPBL	ENST00000652901.1 link	c.6955-9dupT	splice_region_variant, intron_variant	Intron 40 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.000181

AC:

AN:

148962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000735

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000586

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.000204

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000239

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00419

AC:

525

AN:

125324

AF XY:

0.00407

show subpopulations

Gnomad AFR exome

AF:

0.00159

Gnomad AMR exome

AF:

0.00782

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.00526

Gnomad FIN exome

AF:

0.000821

Gnomad NFE exome

AF:

0.00363

Gnomad OTH exome

AF:

0.00275

GnomAD4 exome

AF:

0.0101

AC:

10704

AN:

1058552

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

5023

AN XY:

529704

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00849

AC:

205

AN:

24142

American (AMR)

AF:

0.00457

AC:

154

AN:

33704

Ashkenazi Jewish (ASJ)

AF:

0.00493

AC:

AN:

18648

East Asian (EAS)

AF:

0.00387

AC:

111

AN:

28708

South Asian (SAS)

AF:

0.00570

AC:

365

AN:

64040

European-Finnish (FIN)

AF:

0.00106

AC:

AN:

42560

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

4586

European-Non Finnish (NFE)

AF:

0.0117

AC:

9335

AN:

798608

Other (OTH)

AF:

0.00849

AC:

370

AN:

43556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

1543

3086

4629

6172

7715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000181

AC:

AN:

149054

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

AN XY:

72658

show subpopulations

African (AFR)

AF:

0.0000733

AC:

AN:

40938

American (AMR)

AF:

0.000134

AC:

AN:

14876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.000588

AC:

AN:

5102

South Asian (SAS)

AF:

0.000213

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.000204

AC:

AN:

9798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000239

AC:

AN:

66952

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0124

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Orofacial cleft 1

Uncertain:1

Nov 22, 2022

Grupo de Genetica Humana, Facultad de Medicina - Universidad de La Sabana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

VUS predicted to be pathogenic by its phyloP score in intron 40 of NIPBL, a gene implicated in morphogenetic processes, development of reproductive structures and sister chromatid cohesion, with a known association with Cornelia de Lange syndrome 1, a condition marked by atypical facial features (such as cleft palate), stunted growth, deformities in the limbs, and cognitive impairment. -

Cornelia de Lange syndrome 1

Benign:1

Jun 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.23

La Branchor

0.34

BranchPoint Hunter

4.0

Mutation Taster

=100/0

polymorphism

(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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5-37051759-A-AT

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