NM_133433.4:c.-265A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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. Variant has been reported in ClinVar as Uncertain significance (★).

• 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 -9 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.-265A>G		5_prime_UTR	Exon 1 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.-265A>G		5_prime_UTR	Exon 1 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.-265A>G		5_prime_UTR	Exon 1 of 46	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.-265A>G		5_prime_UTR	Exon 1 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.-265A>G		5_prime_UTR	Exon 1 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.-265A>G		5_prime_UTR	Exon 1 of 46	ENSP00000499536.1	A0A590UJS4

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cornelia de Lange syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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;