rs797045759

Positions:

• chr5-37010067-AT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000282516.13(NIPBL):​c.4422-12del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,581,336 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (7 hom.)
• Consequence: NIPBL ENST00000282516.13 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-37010067-AT-A is Benign according to our data. Variant chr5-37010067-AT-A is described in ClinVar as [Benign]. Clinvar id is 211635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37010067-AT-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00102 (155/152162) while in subpopulation NFE AF= 0.0016 (109/67990). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.4422-12del		intron_variant		ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.4422-12del		intron_variant		1	NM_133433.4	ENSP00000282516	P1
NIPBL	ENST00000448238.2	c.4422-12del		intron_variant		1		ENSP00000406266
NIPBL	ENST00000652901.1	c.4422-12del		intron_variant				ENSP00000499536

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00142 AC: 354 AN: 249898 Hom.: 2 AF XY: 0.00155 AC XY: 209 AN XY: 135138

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00149 AC: 2133 AN: 1429174 Hom.: 7 Cov.: 27 AF XY: 0.00146 AC XY: 1038 AN XY: 713356

Gnomad4 AFR exome AF: 0.000549

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.000732

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74388

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00302 Hom.: 1

Bravo AF: 0.00133

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs797045759; hg19: chr5-37010169;