5-36876823-TC-TCCCCCCC

Variant names:

• chr5-36876823-T-TCCCCCC
• rs376839773
• NM_133433.4:c.-434_-429dupCCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_133433.4(NIPBL):​c.-434_-429dupCCCCCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-434_-429dupCCCCCC		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.-434_-429dupCCCCCC		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 575 AN: 123120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00390

Gnomad ASJ AF: 0.00267

Gnomad EAS AF: 0.000737

Gnomad SAS AF: 0.00162

Gnomad FIN AF: 0.00663

Gnomad MID AF: 0.00373

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00737

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000131 AC: 3 AN: 229680 Hom.: 0 Cov.: 0 AF XY: 0.00000854 AC XY: 1 AN XY: 117050

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

African (AFR) AF: 0.00 AC: 0 AN: 6458

American (AMR) AF: 0.00 AC: 0 AN: 6846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8296

East Asian (EAS) AF: 0.0000470 AC: 1 AN: 21282

South Asian (SAS) AF: 0.00 AC: 0 AN: 2884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1186

European-Non Finnish (NFE) AF: 0.0000136 AC: 2 AN: 147294

Other (OTH) AF: 0.00 AC: 0 AN: 15038

⚠️ 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 AF: 0.00466 AC: 574 AN: 123182 Hom.: 0 Cov.: 31 AF XY: 0.00465 AC XY: 277 AN XY: 59592

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

African (AFR) AF: 0.00477 AC: 154 AN: 32254

American (AMR) AF: 0.00389 AC: 49 AN: 12584

Ashkenazi Jewish (ASJ) AF: 0.00267 AC: 8 AN: 2996

East Asian (EAS) AF: 0.000739 AC: 3 AN: 4060

South Asian (SAS) AF: 0.00162 AC: 6 AN: 3702

European-Finnish (FIN) AF: 0.00663 AC: 54 AN: 8150

Middle Eastern (MID) AF: 0.00403 AC: 1 AN: 248

European-Non Finnish (NFE) AF: 0.00506 AC: 288 AN: 56868

Other (OTH) AF: 0.00668 AC: 11 AN: 1646

⚠️ 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: 0.0000613 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs376839773; hg19: chr5-36876925;