5-36976406-AAAT-A

Position:

• chr5-36976406-AAAT-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.1495+8_1495+10del variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,602,806 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (5 hom.)
• Consequence: NIPBL ENST00000282516.13 splice_donor_5th_base, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.43

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 5-36976406-AAAT-A is Benign according to our data. Variant chr5-36976406-AAAT-A is described in ClinVar as [Likely_benign]. Clinvar id is 96330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36976406-AAAT-A is described in Lovd as [Likely_benign]. Variant chr5-36976406-AAAT-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00198 (302/152280) while in subpopulation NFE AF= 0.00304 (207/68018). AF 95% confidence interval is 0.0027. There are 0 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 302 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.1495+8_1495+10del		splice_donor_5th_base_variant, intron_variant		ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.1495+8_1495+10del		splice_donor_5th_base_variant, intron_variant		1	NM_133433.4	ENSP00000282516	P1
NIPBL	ENST00000448238.2	c.1495+8_1495+10del		splice_donor_5th_base_variant, intron_variant		1		ENSP00000406266
NIPBL	ENST00000652901.1	c.1495+8_1495+10del		splice_donor_5th_base_variant, intron_variant				ENSP00000499536
NIPBL	ENST00000504430.5	n.1115+8_1115+10del		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00206 AC: 487 AN: 236396 Hom.: 1 AF XY: 0.00191 AC XY: 247 AN XY: 129478

Gnomad AFR exome AF: 0.000593

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.000444

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00297 AC: 4310 AN: 1450526 Hom.: 5 AF XY: 0.00285 AC XY: 2061 AN XY: 721892

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000867

Gnomad4 NFE exome AF: 0.00350

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74450

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00298 Hom.: 0

Bravo AF: 0.00192

EpiCase AF: 0.00289

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	NIPBL: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cornelia de Lange syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

De Lange syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs398124464; hg19: chr5-36976508;