5-37036347-GTATATATATATA-GTATATATATATATA

Variant names:

• chr5-37036347-G-GTA
• rs10554564
• NM_133433.4:c.5863-12_5863-11dupAT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_133433.4(NIPBL):​c.5863-12_5863-11dupAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0079 (6 hom., cov: 0)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 -9 ACMG points.

• BP6: Variant 5-37036347-G-GTA is Benign according to our data. Variant chr5-37036347-G-GTA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96347.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00793 (1079/135980) while in subpopulation SAS AF = 0.0175 (75/4284). AF 95% confidence interval is 0.0143. There are 6 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1079 AD gene.

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.5863-12_5863-11dupAT		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.5863-12_5863-11dupAT		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.5863-12_5863-11dupAT		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.5863-32_5863-31insTA		intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.5863-32_5863-31insTA		intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.5863-32_5863-31insTA		intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00793 AC: 1079 AN: 135986 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00579

Gnomad AMR AF: 0.00390

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00345

Gnomad NFE AF: 0.00655

Gnomad OTH AF: 0.00655

GnomAD2 exomes AF: 0.0307 AC: 1011 AN: 32888 AF XY: 0.0341

Gnomad AFR exome AF: 0.00654

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.0288

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0263 AC: 6378 AN: 242628 Hom.: 0 Cov.: 0 AF XY: 0.0278 AC XY: 3686 AN XY: 132528

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

African (AFR) AF: 0.0183 AC: 79 AN: 4322

American (AMR) AF: 0.0171 AC: 88 AN: 5140

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 148 AN: 6546

East Asian (EAS) AF: 0.0270 AC: 259 AN: 9578

South Asian (SAS) AF: 0.0369 AC: 372 AN: 10074

European-Finnish (FIN) AF: 0.0137 AC: 275 AN: 20022

Middle Eastern (MID) AF: 0.0164 AC: 14 AN: 854

European-Non Finnish (NFE) AF: 0.0277 AC: 4851 AN: 175286

Other (OTH) AF: 0.0270 AC: 292 AN: 10806

⚠️ 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 AF: 0.00793 AC: 1079 AN: 135980 Hom.: 6 Cov.: 0 AF XY: 0.00763 AC XY: 498 AN XY: 65258

African (AFR) AF: 0.0112 AC: 414 AN: 36828

American (AMR) AF: 0.00390 AC: 52 AN: 13334

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 10 AN: 3312

East Asian (EAS) AF: 0.0169 AC: 80 AN: 4724

South Asian (SAS) AF: 0.0175 AC: 75 AN: 4284

European-Finnish (FIN) AF: 0.00179 AC: 12 AN: 6686

Middle Eastern (MID) AF: 0.00370 AC: 1 AN: 270

European-Non Finnish (NFE) AF: 0.00655 AC: 418 AN: 63834

Other (OTH) AF: 0.00651 AC: 12 AN: 1844

Alfa AF: 0.00366 Hom.: 457

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.012
Mutation Taster		=100/0	polymorphism

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;