5-37048613-TAAA-TAA

Variant names:

• chr5-37048613-TA-T
• rs797045778
• NM_133433.4:c.6707delA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_133433.4(NIPBL):​c.6707delA​(p.Asn2236ThrfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,138 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NIPBL NM_133433.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6707delA	p.Asn2236ThrfsTer29	frameshift_variant	Exon 39 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6707delA	p.Asn2236ThrfsTer29	frameshift_variant	Exon 39 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6707delA	p.Asn2236ThrfsTer29	frameshift_variant	Exon 39 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6707delA	p.Asn2236ThrfsTer29	frameshift_variant	Exon 39 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456138 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724496

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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: rs797045778; hg19: chr5-37048715;