5-36877098-A-AC

Position:

• chr5-36877098-A-AC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_133433.4(NIPBL):​c.-153dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000783 in 319,110 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.-153dup		5_prime_UTR_variant	1/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.-153dup		5_prime_UTR_variant	1/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.-153dup		5_prime_UTR_variant	1/46	1
NIPBL	ENST00000652901.1	c.-153dup		5_prime_UTR_variant	1/46

Frequencies

GnomAD3 genomes AF: 0.0000487 AC: 7 AN: 143716 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000306

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000970 AC: 17 AN: 175284 Hom.: 0 Cov.: 0 AF XY: 0.0000778 AC XY: 7 AN XY: 90010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000495

Gnomad4 NFE exome AF: 0.0000705

Gnomad4 OTH exome AF: 0.0000870

GnomAD4 genome AF: 0.0000556 AC: 8 AN: 143826 Hom.: 0 Cov.: 31 AF XY: 0.0000713 AC XY: 5 AN XY: 70090

Gnomad4 AFR AF: 0.0000772

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000214

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000105

Gnomad4 NFE AF: 0.0000306

Gnomad4 OTH AF: 0.000501

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

De Lange syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs567891305; hg19: chr5-36877200;