5-36876993-A-G

Variant names:

• chr5-36876993-A-G
• rs879291582
• NM_133433.4:c.-265A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_133433.4(NIPBL):​c.-265A>G variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.000159 in 383,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24
• 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 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000113 (17/150220) while in subpopulation NFE AF = 0.000252 (17/67504). AF 95% confidence interval is 0.00016. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-265A>G		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.-265A>G		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-265A>G		5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-265A>G		5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 150220 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000188 AC: 44 AN: 233528 Hom.: 0 Cov.: 0 AF XY: 0.000143 AC XY: 17 AN XY: 119020

African (AFR) AF: 0.000304 AC: 2 AN: 6574

American (AMR) AF: 0.000430 AC: 3 AN: 6978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8570

East Asian (EAS) AF: 0.00 AC: 0 AN: 21648

South Asian (SAS) AF: 0.00 AC: 0 AN: 2916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1268

European-Non Finnish (NFE) AF: 0.000247 AC: 37 AN: 149590

Other (OTH) AF: 0.000130 AC: 2 AN: 15368

GnomAD4 genome AF: 0.000113 AC: 17 AN: 150220 Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 8 AN XY: 73326

African (AFR) AF: 0.00 AC: 0 AN: 40718

American (AMR) AF: 0.00 AC: 0 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.000252 AC: 17 AN: 67504

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.000214 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	-0.56
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		4.2
PromoterAI		0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879291582; hg19: chr5-36877095;