5-37051759-ATTTT-ATTT

Position:

• chr5-37051759-ATTTT-ATTT

Variant summary

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

The NM_133433.4(NIPBL):​c.6955-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,117,266 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.023 (0 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.231

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-37051759-AT-A is Benign according to our data. Variant chr5-37051759-AT-A is described in ClinVar as [Benign]. Clinvar id is 197446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00166 (248/148958) while in subpopulation AFR AF= 0.00508 (208/40930). AF 95% confidence interval is 0.00452. There are 1 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6955-9delT		intron_variant		ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6955-9delT		intron_variant		1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6955-9delT		intron_variant		1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6955-9delT		intron_variant				ENSP00000499536.1
NIPBL	ENST00000514335.1	n.828delT		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 249 AN: 148868 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000409

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00147

GnomAD4 exome AF: 0.0232 AC: 22468 AN: 968308 Hom.: 0 Cov.: 18 AF XY: 0.0220 AC XY: 10602 AN XY: 482738

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.0174

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0224

GnomAD4 genome AF: 0.00166 AC: 248 AN: 148958 Hom.: 1 Cov.: 32 AF XY: 0.00186 AC XY: 135 AN XY: 72606

Gnomad4 AFR AF: 0.00508

Gnomad4 AMR AF: 0.00108

Gnomad4 ASJ AF: 0.000292

Gnomad4 EAS AF: 0.000784

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.000409

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00146

Asia WGS AF: 0.0150 AC: 52 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -

Cornelia de Lange syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
La Branchor		0.34
BranchPoint Hunter		4.0

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: rs757731487; hg19: chr5-37051861;