rs1554029659

Variant names:

• chr5-37036361-ATATATATG-A
• rs1554029659
• NM_133433.4:c.5863-10_5863-3delGTATATAT

Your query was ambiguous. Multiple possible variants found:

• chr5-37036361-ATATATATG-A
• chr5-37036361-ATATATATG-ATATATATGTATATATG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133433.4(NIPBL):​c.5863-10_5863-3delGTATATAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 401,946 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• 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 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.5863-10_5863-3delGTATATAT		splice_region intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.5863-10_5863-3delGTATATAT		splice_region intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.5863-10_5863-3delGTATATAT		splice_region intron	N/A	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.5863-17_5863-10delTATATATG		intron	N/A	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.5863-17_5863-10delTATATATG		intron	N/A	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.5863-17_5863-10delTATATATG		intron	N/A	ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000249 AC: 1 AN: 401946 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 213110

⚠️ 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: 8466

American (AMR) AF: 0.00 AC: 0 AN: 7756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9756

East Asian (EAS) AF: 0.00 AC: 0 AN: 14408

South Asian (SAS) AF: 0.00 AC: 0 AN: 15770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1320

European-Non Finnish (NFE) AF: 0.00000331 AC: 1 AN: 301684

Other (OTH) AF: 0.00 AC: 0 AN: 17904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

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

Other links and lift over

dbSNP: rs1554029659; hg19: chr5-37036463;