Genetic Variant NIPBL:c.6955-15_6955-9dupTTTTTTT (chr5-37051759-A-ATTTTTTT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133433.4(NIPBL):c.6955-15_6955-9dupTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000272 in 1,103,388 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.6955-15_6955-9dupTTTTTTT		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.6955-15_6955-9dupTTTTTTT	splice_region_variant, intron_variant	Intron 40 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.6955-15_6955-9dupTTTTTTT	splice_region_variant, intron_variant	Intron 40 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000514335.1 link	n.822_828dupTTTTTTT	non_coding_transcript_exon_variant	Exon 1 of 7	2
NIPBL	ENST00000652901.1 link	c.6955-15_6955-9dupTTTTTTT	splice_region_variant, intron_variant	Intron 40 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000272

AC:

AN:

1103388

Hom.:

Cov.:

AF XY:

0.00000362

AC XY:

AN XY:

552562

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25220

American (AMR)

AF:

0.00

AC:

AN:

35450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19762

East Asian (EAS)

AF:

0.00

AC:

AN:

30226

South Asian (SAS)

AF:

0.00

AC:

AN:

67284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43954

Middle Eastern (MID)

AF:

0.000211

AC:

AN:

4742

European-Non Finnish (NFE)

AF:

0.00000241

AC:

AN:

831196

Other (OTH)

AF:

0.00

AC:

AN:

45554

⚠️ 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: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000182

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.23

La Branchor

0.34

BranchPoint Hunter

4.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-37051759-ATTTTT-ATTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over