5-36876791-C-T

Variant names:

• chr5-36876791-C-T
• rs1251456909
• NM_133433.4:c.-467C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_133433.4(NIPBL):​c.-467C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPBL NM_133433.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.87
• Publications: 1 publications found

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-DT (HGNC:51293): (NIPBL divergent transcript)

ENSG00000304702 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-36876791-C-T is Pathogenic according to our data. Variant chr5-36876791-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1195876.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-467C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 47	ENST00000282516.13	NP_597677.2
NIPBL	NM_133433.4	c.-467C>T		5_prime_UTR_variant	Exon 1 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.-467C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000282516.13	c.-467C>T		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 245466 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124570

African (AFR) AF: 0.00 AC: 0 AN: 7116

American (AMR) AF: 0.00 AC: 0 AN: 7382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9138

East Asian (EAS) AF: 0.00 AC: 0 AN: 22762

South Asian (SAS) AF: 0.00 AC: 0 AN: 3026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 157324

Other (OTH) AF: 0.00 AC: 0 AN: 16236

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:2

May 17, 2019

Cell and Gene Engineering Laboratory, Zhejiang University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A heterozygous mutation (c.-467C>T) in the coding region of the NIPBL gene has been reported in a boy with Cornelia de Lange syndrome. Additionally, in vitro functional studies indicated that the variant significantly decreased the transcription activity of NIPBL. In summary, this results indicates classification of this variant as pathogenic. -

Feb 11, 2022

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This NM_133433.4:c.-467C>T, p.? (Chr5:36876893C>T) variant creates an ATG with strong in silico predictions of a use as an alternative translation initiation site with a putative uORF, is located 11-bp upstream from the c.-457_-456delinsAT variant that we assessed here, occurred de novo in a patient with classic CdLS, and was very recently reported in another CdLS patient in the Clinvar database, classified as pathogenic by the Cell and Gene Engineering Laboratory, Zhejiang University (evidence not provided in Clinvar, accession number: SCV001775539). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.95
PhyloP100		2.9
PromoterAI		-0.33	Neutral
Mutation Taster		=265/35	polymorphism

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

Other links and lift over

dbSNP: rs1251456909; hg19: chr5-36876893;