5-37064967-CAAA-CAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):c.*84dup variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000805 in 1,530,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: NIPBL NM_133433.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.35

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 -16 ACMG points.

• BP6: Variant 5-37064967-C-CA is Benign according to our data. Variant chr5-37064967-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 211619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000904 (135/149400) while in subpopulation EAS AF= 0.00371 (19/5122). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.*84dup		3_prime_UTR_variant	47/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.*84dup		3_prime_UTR_variant	47/47	1	NM_133433.4	P1
NIPBL	ENST00000652901.1	c.*443dup		3_prime_UTR_variant	46/46
NIPBL	ENST00000514335.1	n.2422dup		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.000904 AC: 135 AN: 149288 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00180

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00370

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000550

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000795 AC: 1097 AN: 1380626 Hom.: 0 Cov.: 23 AF XY: 0.000781 AC XY: 538 AN XY: 689206

Gnomad4 AFR exome AF: 0.00145

Gnomad4 AMR exome AF: 0.000840

Gnomad4 ASJ exome AF: 0.0000405

Gnomad4 EAS exome AF: 0.00213

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.000185

Gnomad4 NFE exome AF: 0.000714

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000904 AC: 135 AN: 149400 Hom.: 0 Cov.: 32 AF XY: 0.000907 AC XY: 66 AN XY: 72774

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00180

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00371

Gnomad4 SAS AF: 0.00128

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000550

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

De Lange syndrome Benign:1

Likely benign, 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: rs587783876; hg19: chr5-37065069;