5-36876834-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133433.4(NIPBL):c.-424T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.32 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.976

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.-424T>C		5_prime_UTR_variant	1/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.-424T>C		5_prime_UTR_variant	1/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.-424T>C		5_prime_UTR_variant	1/46	1
NIPBL	ENST00000652901.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 16619 AN: 51672 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.202

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.340

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00435 AC: 78 AN: 17922 Hom.: 0 Cov.: 0 AF XY: 0.00366 AC XY: 34 AN XY: 9290

Gnomad4 AFR exome AF: 0.00503

Gnomad4 AMR exome AF: 0.00628

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.322 AC: 16627 AN: 51710 Hom.: 0 Cov.: 0 AF XY: 0.307 AC XY: 7515 AN XY: 24512

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.338

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Benign	0.64

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: rs886060552; hg19: chr5-36876936;