rs298972

Variant names:

• chr5-37007994-T-G
• rs298972
• NM_133433.4:c.4240-14T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133433.4(NIPBL):​c.4240-14T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,523,158 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (75 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (70 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.582
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-37007994-T-G is Benign according to our data. Variant chr5-37007994-T-G is described in ClinVar as Benign. ClinVar VariationId is 159108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0597 is higher than 0.05.

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.4240-14T>G		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.4240-14T>G		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.4240-14T>G		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.4240-14T>G		intron	N/A	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.4240-14T>G		intron	N/A	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.4240-14T>G		intron	N/A	ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2687 AN: 152068 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00471 AC: 1179 AN: 250438 AF XY: 0.00343

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00177 AC: 2431 AN: 1370972 Hom.: 70 Cov.: 24 AF XY: 0.00146 AC XY: 1006 AN XY: 687384

African (AFR) AF: 0.0625 AC: 1979 AN: 31642

American (AMR) AF: 0.00386 AC: 172 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.00 AC: 0 AN: 39062

South Asian (SAS) AF: 0.000119 AC: 10 AN: 84354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00215 AC: 12 AN: 5578

European-Non Finnish (NFE) AF: 0.0000282 AC: 29 AN: 1029652

Other (OTH) AF: 0.00400 AC: 229 AN: 57308

GnomAD4 genome AF: 0.0177 AC: 2689 AN: 152186 Hom.: 75 Cov.: 32 AF XY: 0.0167 AC XY: 1245 AN XY: 74420

African (AFR) AF: 0.0617 AC: 2564 AN: 41544

American (AMR) AF: 0.00589 AC: 90 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67928

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0105 Hom.: 11

Bravo AF: 0.0204

Asia WGS AF: 0.00289 AC: 10 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Cornelia de Lange syndrome 1 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.50
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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: rs298972; hg19: chr5-37008096;