5-36876834-T-TC

Position:

• chr5-36876834-T-TC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_133433.4(NIPBL):​c.-416dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 80,170 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (0 hom., cov: 25)
  • Exomes 𝑓: 0.046 (2 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.57

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 -9 ACMG points.

• BP6: Variant 5-36876834-T-TC is Benign according to our data. Variant chr5-36876834-T-TC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 353362.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-416dup		5_prime_UTR_variant	1/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.-416dup		5_prime_UTR_variant	1/47	1	NM_133433.4	ENSP00000282516	P1
NIPBL	ENST00000448238.2	c.-416dup		5_prime_UTR_variant	1/46	1		ENSP00000406266
NIPBL	ENST00000652901.1			upstream_gene_variant				ENSP00000499536

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 330 AN: 61944 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000732

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00852

Gnomad OTH AF: 0.00426

GnomAD4 exome AF: 0.0459 AC: 834 AN: 18172 Hom.: 2 Cov.: 0 AF XY: 0.0451 AC XY: 426 AN XY: 9436

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00326

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0591

Gnomad4 OTH exome AF: 0.0550

GnomAD4 genome AF: 0.00532 AC: 330 AN: 61998 Hom.: 0 Cov.: 25 AF XY: 0.00504 AC XY: 149 AN XY: 29542

Gnomad4 AFR AF: 0.00230

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000731

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00181

Gnomad4 NFE AF: 0.00852

Gnomad4 OTH AF: 0.00424

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

De Lange syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

NIPBL: BS1 -

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: rs886060553; hg19: chr5-36876936;