5-36876830-G-C

Variant summary

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

The NM_133433.4(NIPBL):c.-428G>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 0.29 (0 hom., cov: 9)
  • Exomes 𝑓: 0.00064 (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: 1.14

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=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.-428G>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.-428G>C		5_prime_UTR_variant	1/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.-428G>C		5_prime_UTR_variant	1/46	1
NIPBL	ENST00000652901.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 16670 AN: 58040 Hom.: 0 Cov.: 9 FAILED QC

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.314

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000642 AC: 93 AN: 144898 Hom.: 0 Cov.: 0 AF XY: 0.000594 AC XY: 44 AN XY: 74128

Gnomad4 AFR exome AF: 0.000799

Gnomad4 AMR exome AF: 0.000724

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00352

Gnomad4 SAS exome AF: 0.000971

Gnomad4 FIN exome AF: 0.0000645

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.000650

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.287 AC: 16674 AN: 58066 Hom.: 0 Cov.: 9 AF XY: 0.271 AC XY: 7522 AN XY: 27776

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.312

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	-0.67
Cadd	Benign	15
Dann	Benign	0.71

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: rs886060551; hg19: chr5-36876932;