rs293748

Positions:

• chr5-36900741-G-A
• chr5-36900741-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133433.4(NIPBL):​c.-80+23563G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 151,860 control chromosomes in the GnomAD database, including 2,163 homozygotes. 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 0.15 (2163 hom., cov: 31)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-80+23563G>A		intron_variant		ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.-80+23563G>A		intron_variant		1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-80+23563G>A		intron_variant		1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-80+23563G>A		intron_variant				ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23137 AN: 151742 Hom.: 2162 Cov.: 31

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.152 AC: 23136 AN: 151860 Hom.: 2163 Cov.: 31 AF XY: 0.157 AC XY: 11635 AN XY: 74220

Gnomad4 AFR AF: 0.0567

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.175

Alfa AF: 0.180 Hom.: 3412

Bravo AF: 0.144

Asia WGS AF: 0.261 AC: 907 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs293748; hg19: chr5-36900843;