5-37036347-GTATATATATATA-GTATATATATATATATATATATATA

Variant names:

• chr5-37036347-G-GTATATATATATA
• rs10554564
• NM_133433.4:c.5863-22_5863-11dupATATATATATAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_133433.4(NIPBL):​c.5863-22_5863-11dupATATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0120
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000118 (16/136030) while in subpopulation NFE AF = 0.000235 (15/63874). AF 95% confidence interval is 0.000145. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.5863-22_5863-11dupATATATATATAT		intron_variant	Intron 32 of 46	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.5863-32_5863-31insTATATATATATA		intron_variant	Intron 32 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.5863-32_5863-31insTATATATATATA		intron_variant	Intron 32 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.5863-32_5863-31insTATATATATATA		intron_variant	Intron 32 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 16 AN: 136030 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000546

GnomAD4 exome AF: 0.0000402 AC: 10 AN: 248474 Hom.: 0 Cov.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135716

⚠️ 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: 4370

American (AMR) AF: 0.000192 AC: 1 AN: 5214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6686

East Asian (EAS) AF: 0.00 AC: 0 AN: 9774

South Asian (SAS) AF: 0.00 AC: 0 AN: 10280

European-Finnish (FIN) AF: 0.0000476 AC: 1 AN: 21026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 864

European-Non Finnish (NFE) AF: 0.0000446 AC: 8 AN: 179286

Other (OTH) AF: 0.00 AC: 0 AN: 10974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002271), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000118 AC: 16 AN: 136030 Hom.: 0 Cov.: 0 AF XY: 0.0000460 AC XY: 3 AN XY: 65264

African (AFR) AF: 0.00 AC: 0 AN: 36784

American (AMR) AF: 0.00 AC: 0 AN: 13328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4744

South Asian (SAS) AF: 0.00 AC: 0 AN: 4310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000235 AC: 15 AN: 63874

Other (OTH) AF: 0.000546 AC: 1 AN: 1832

Alfa AF: 0.000271 Hom.: 457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.012

Splicing

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

Other links and lift over

dbSNP: rs10554564; hg19: chr5-37036449;