5-36876830-G-C

Variant names:

• chr5-36876830-G-C
• rs886060551
• NM_133433.4:c.-428G>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.-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
• 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-428G>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.-428G>C		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8

Frequencies

GnomAD3 genomes AF: 0.287 AC: 16670 AN: 58040 Hom.: 0 Cov.: 9

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

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

African (AFR) AF: 0.000799 AC: 3 AN: 3754

American (AMR) AF: 0.000724 AC: 3 AN: 4144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4994

East Asian (EAS) AF: 0.00352 AC: 48 AN: 13624

South Asian (SAS) AF: 0.000971 AC: 2 AN: 2060

European-Finnish (FIN) AF: 0.0000645 AC: 1 AN: 15514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 748

European-Non Finnish (NFE) AF: 0.000330 AC: 30 AN: 90832

Other (OTH) AF: 0.000650 AC: 6 AN: 9228

⚠️ 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: 0.287 AC: 16674 AN: 58066 Hom.: 0 Cov.: 9 AF XY: 0.271 AC XY: 7522 AN XY: 27776

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

African (AFR) AF: 0.287 AC: 4388 AN: 15282

American (AMR) AF: 0.243 AC: 1303 AN: 5352

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 463 AN: 1434

East Asian (EAS) AF: 0.195 AC: 338 AN: 1736

South Asian (SAS) AF: 0.197 AC: 346 AN: 1760

European-Finnish (FIN) AF: 0.207 AC: 753 AN: 3642

Middle Eastern (MID) AF: 0.184 AC: 18 AN: 98

European-Non Finnish (NFE) AF: 0.316 AC: 8736 AN: 27644

Other (OTH) AF: 0.312 AC: 251 AN: 804

⚠️ 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	-0.67
CADD	Benign	15
DANN	Benign	0.71
PhyloP100		1.1
PromoterAI		0.0052	Neutral
Mutation Taster		=272/28	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: rs886060551; hg19: chr5-36876932;