rs797045759

Variant names:

• chr5-37010067-AT-A
• rs797045759
• NM_133433.4:c.4422-12delT

Your query was ambiguous. Multiple possible variants found:

• chr5-37010067-AT-A
• chr5-37010067-AT-ATT

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.4422-12delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,581,336 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (7 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.32
• 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 5-37010067-AT-A is Benign according to our data. Variant chr5-37010067-AT-A is described in ClinVar as Benign. ClinVar VariationId is 211635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00102 (155/152162) while in subpopulation NFE AF = 0.0016 (109/67990). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 155 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.4422-12delT		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.4422-12delT		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.4422-12delT		intron	N/A	NP_056199.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.4422-19delT		intron	N/A	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.4422-19delT		intron	N/A	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.4422-19delT		intron	N/A	ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00142 AC: 354 AN: 249898 AF XY: 0.00155

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00149 AC: 2133 AN: 1429174 Hom.: 7 Cov.: 27 AF XY: 0.00146 AC XY: 1038 AN XY: 713356

African (AFR) AF: 0.000549 AC: 18 AN: 32790

American (AMR) AF: 0.00105 AC: 47 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 92 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85504

European-Finnish (FIN) AF: 0.000732 AC: 39 AN: 53274

Middle Eastern (MID) AF: 0.0125 AC: 68 AN: 5438

European-Non Finnish (NFE) AF: 0.00160 AC: 1731 AN: 1083176

Other (OTH) AF: 0.00213 AC: 126 AN: 59170

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74388

African (AFR) AF: 0.000241 AC: 10 AN: 41538

American (AMR) AF: 0.000917 AC: 14 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 67990

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00302 Hom.: 1

Bravo AF: 0.00133

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)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797045759; hg19: chr5-37010169; COSMIC: COSV56957536;