5-37036347-GTATATATATATA-GTATATATA

Variant names:

• chr5-37036347-GTATA-G
• rs10554564
• NM_133433.4:c.5863-14_5863-11delATAT

Variant summary

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

The NM_133433.4(NIPBL):​c.5863-14_5863-11delATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 374,450 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: 𝑓 0.00036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• 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 amr. GnomAd4 allele frequency = 0.00036 (49/135974) while in subpopulation AMR AF = 0.000975 (13/13336). AF 95% confidence interval is 0.000576. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.5863-14_5863-11delATAT		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.5863-31_5863-28delTATA		intron_variant	Intron 32 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.5863-31_5863-28delTATA		intron_variant	Intron 32 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.5863-31_5863-28delTATA		intron_variant	Intron 32 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.000353 AC: 48 AN: 135982 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000976

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000422

Gnomad SAS AF: 0.000464

Gnomad FIN AF: 0.000150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000172

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0369 AC: 1214 AN: 32888 AF XY: 0.0393

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.0769

Gnomad ASJ exome AF: 0.0496

Gnomad EAS exome AF: 0.0654

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0486

GnomAD4 exome AF: 0.0292 AC: 6957 AN: 238476 Hom.: 0 AF XY: 0.0295 AC XY: 3845 AN XY: 130222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0670 AC: 272 AN: 4058

American (AMR) AF: 0.0619 AC: 300 AN: 4848

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 289 AN: 6346

East Asian (EAS) AF: 0.0414 AC: 388 AN: 9372

South Asian (SAS) AF: 0.0463 AC: 451 AN: 9742

European-Finnish (FIN) AF: 0.0124 AC: 240 AN: 19366

Middle Eastern (MID) AF: 0.0661 AC: 53 AN: 802

European-Non Finnish (NFE) AF: 0.0265 AC: 4591 AN: 173420

Other (OTH) AF: 0.0354 AC: 373 AN: 10522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000360 AC: 49 AN: 135974 Hom.: 0 Cov.: 0 AF XY: 0.000291 AC XY: 19 AN XY: 65252

African (AFR) AF: 0.000543 AC: 20 AN: 36810

American (AMR) AF: 0.000975 AC: 13 AN: 13336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3312

East Asian (EAS) AF: 0.000423 AC: 2 AN: 4724

South Asian (SAS) AF: 0.000467 AC: 2 AN: 4286

European-Finnish (FIN) AF: 0.000150 AC: 1 AN: 6688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000172 AC: 11 AN: 63842

Other (OTH) AF: 0.00 AC: 0 AN: 1842

Alfa AF: 0.00 Hom.: 457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs10554564; hg19: chr5-37036449;