5-36876834-T-C

Variant names:

• chr5-36876834-T-C
• rs886060552
• NM_133433.4:c.-424T>C

Variant summary

Our verdict is Likely benign. The variant received -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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 0 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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-424T>C		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.-424T>C		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8

Frequencies

GnomAD3 genomes AF: 0.322 AC: 16619 AN: 51672 Hom.: 0 Cov.: 0

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00503 AC: 2 AN: 398

American (AMR) AF: 0.00628 AC: 3 AN: 478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 468

East Asian (EAS) AF: 0.0224 AC: 39 AN: 1738

South Asian (SAS) AF: 0.00298 AC: 1 AN: 336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.00250 AC: 29 AN: 11590

Other (OTH) AF: 0.00353 AC: 4 AN: 1134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.315 AC: 4392 AN: 13932

American (AMR) AF: 0.260 AC: 1282 AN: 4938

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 454 AN: 1268

East Asian (EAS) AF: 0.284 AC: 343 AN: 1206

South Asian (SAS) AF: 0.302 AC: 355 AN: 1174

European-Finnish (FIN) AF: 0.236 AC: 767 AN: 3248

Middle Eastern (MID) AF: 0.212 AC: 17 AN: 80

European-Non Finnish (NFE) AF: 0.349 AC: 8698 AN: 24896

Other (OTH) AF: 0.338 AC: 246 AN: 728

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.98
PromoterAI		-0.11	Neutral
Mutation Taster		=296/4	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: rs886060552; hg19: chr5-36876936;