NM_133433.4:c.6955-9delT

Variant names:

• chr5-37051759-AT-A
• rs757731487
• NM_133433.4:c.6955-9delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):​c.6955-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,117,266 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.023 (0 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.231
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 5-37051759-AT-A is Benign according to our data. Variant chr5-37051759-AT-A is described in ClinVar as Benign. ClinVar VariationId is 197446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00166 (248/148958) while in subpopulation AFR AF = 0.00508 (208/40930). AF 95% confidence interval is 0.00452. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 248 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.6955-9delT		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.6955-9delT		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.6955-9delT		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.6955-9delT		intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.6955-9delT		intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.6955-9delT		intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 249 AN: 148868 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000409

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.0162 AC: 2031 AN: 125324 AF XY: 0.0164

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.0151

Gnomad FIN exome AF: 0.00509

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0232 AC: 22468 AN: 968308 Hom.: 0 Cov.: 18 AF XY: 0.0220 AC XY: 10602 AN XY: 482738

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

African (AFR) AF: 0.0297 AC: 653 AN: 21990

American (AMR) AF: 0.0153 AC: 453 AN: 29576

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 296 AN: 16128

East Asian (EAS) AF: 0.0115 AC: 283 AN: 24696

South Asian (SAS) AF: 0.0174 AC: 977 AN: 56156

European-Finnish (FIN) AF: 0.00594 AC: 226 AN: 38060

Middle Eastern (MID) AF: 0.0149 AC: 64 AN: 4282

European-Non Finnish (NFE) AF: 0.0252 AC: 18641 AN: 738316

Other (OTH) AF: 0.0224 AC: 875 AN: 39104

⚠️ 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: 0.00166 AC: 248 AN: 148958 Hom.: 1 Cov.: 32 AF XY: 0.00186 AC XY: 135 AN XY: 72606

African (AFR) AF: 0.00508 AC: 208 AN: 40930

American (AMR) AF: 0.00108 AC: 16 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3430

East Asian (EAS) AF: 0.000784 AC: 4 AN: 5100

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4702

European-Finnish (FIN) AF: 0.000409 AC: 4 AN: 9768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 66904

Other (OTH) AF: 0.00146 AC: 3 AN: 2060

Alfa AF: 0.0432 Hom.: 0

Asia WGS AF: 0.0150 AC: 52 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cornelia de Lange syndrome 1 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
La Branchor		0.34
BranchPoint Hunter		4.0
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: rs757731487; hg19: chr5-37051861; COSMIC: COSV56941603;