rs797045782

Variant names:

• chr5-37057223-ATCTAGCC-NNNNNNNNNNNNN
• NM_133433.4:c.7301_7308delATCTAGCCinsNNNNNNNNNNNNN

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP2

The NM_133433.4(NIPBL):​c.7301_7308delATCTAGCCinsNNNNNNNNNNNNN​(p.Asn2434fs) variant causes a frameshift, missense change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 N/A (N/A hom., cov:)
  • Exomes 𝑓: N/A (N/A hom.)
• Consequence: NIPBL NM_133433.4 frameshift, missense
• Clinical Significance: Not reported in ClinVar
• Conservation: No conservation score assigned

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_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP2: Missense variant in the NIPBL gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 5.5737 (above the threshold of 3.09). Trascript score misZ: 6.6817 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.7301_7308delATCTAGCCinsNNNNNNNNNNNNN	p.Asn2434fs	frameshift_variant, missense_variant	Exon 43 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.7301_7308delATCTAGCCinsNNNNNNNNNNNNN	p.Asn2434fs	frameshift_variant, missense_variant	Exon 43 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.7301_7308delATCTAGCCinsNNNNNNNNNNNNN	p.Asn2434fs	frameshift_variant, missense_variant	Exon 43 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.7264-1668_7264-1661delATCTAGCCinsNNNNNNNNNNNNN		intron_variant	Intron 42 of 45			ENSP00000499536.1
NIPBL	ENST00000514335.1	n.1183_1190delATCTAGCCinsNNNNNNNNNNNNN		non_coding_transcript_exon_variant	Exon 3 of 7	2

Frequencies

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

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-37057325;