rs76297333

Variant names:

• chr5-37008730-A-G
• rs76297333
• NM_133433.4:c.4421+7A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-37008730-A-G
• chr5-37008730-A-C

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.4421+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 1,431,466 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (83 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (87 hom.)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001526
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.655
• 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=-0.68).
• BP6: Variant 5-37008730-A-G is Benign according to our data. Variant chr5-37008730-A-G is described in ClinVar as Benign. ClinVar VariationId is 96341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.4421+7A>G		splice_region intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.4421+7A>G		splice_region intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.4421+7A>G		splice_region 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.4421+7A>G		splice_region intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.4421+7A>G		splice_region intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.4421+7A>G		splice_region intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3034 AN: 152184 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00791 AC: 1978 AN: 249976 AF XY: 0.00739

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.00560

GnomAD4 exome AF: 0.00511 AC: 6541 AN: 1279164 Hom.: 87 Cov.: 20 AF XY: 0.00520 AC XY: 3359 AN XY: 646180

African (AFR) AF: 0.0666 AC: 1984 AN: 29794

American (AMR) AF: 0.00587 AC: 261 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.000440 AC: 11 AN: 24982

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38694

South Asian (SAS) AF: 0.00933 AC: 770 AN: 82534

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53342

Middle Eastern (MID) AF: 0.0220 AC: 119 AN: 5404

European-Non Finnish (NFE) AF: 0.00313 AC: 2964 AN: 945746

Other (OTH) AF: 0.00782 AC: 424 AN: 54192

GnomAD4 genome AF: 0.0199 AC: 3038 AN: 152302 Hom.: 83 Cov.: 32 AF XY: 0.0195 AC XY: 1452 AN XY: 74480

African (AFR) AF: 0.0622 AC: 2586 AN: 41556

American (AMR) AF: 0.00857 AC: 131 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00933 AC: 45 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 68030

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0104 Hom.: 11

Bravo AF: 0.0231

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.00387

EpiControl AF: 0.00664

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Cornelia de Lange syndrome 1 (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.6
DANN	Benign	0.73
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.010
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: rs76297333; hg19: chr5-37008832;