rs78827246

Variant names:

• chr5-37000972-A-G
• rs78827246
• NM_133433.4:c.3575-17A>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.3575-17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,599,282 control chromosomes in the GnomAD database, including 11,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1223 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10750 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.330
• Publications: 7 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=-0.86).
• BP6: Variant 5-37000972-A-G is Benign according to our data. Variant chr5-37000972-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 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.3575-17A>G		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.3575-17A>G		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.3575-17A>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.3575-17A>G		intron	N/A	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.3575-17A>G		intron	N/A	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.3575-17A>G		intron	N/A	ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18561 AN: 152064 Hom.: 1220 Cov.: 32

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.137 AC: 34357 AN: 250380 AF XY: 0.132

Gnomad AFR exome AF: 0.0929

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.118 AC: 170917 AN: 1447100 Hom.: 10750 Cov.: 28 AF XY: 0.118 AC XY: 85003 AN XY: 720944

African (AFR) AF: 0.0979 AC: 3242 AN: 33112

American (AMR) AF: 0.227 AC: 10132 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5258 AN: 26000

East Asian (EAS) AF: 0.108 AC: 4271 AN: 39464

South Asian (SAS) AF: 0.109 AC: 9381 AN: 85956

European-Finnish (FIN) AF: 0.127 AC: 6786 AN: 53372

Middle Eastern (MID) AF: 0.166 AC: 951 AN: 5712

European-Non Finnish (NFE) AF: 0.112 AC: 123243 AN: 1099006

Other (OTH) AF: 0.128 AC: 7653 AN: 59890

GnomAD4 genome AF: 0.122 AC: 18588 AN: 152182 Hom.: 1223 Cov.: 32 AF XY: 0.125 AC XY: 9313 AN XY: 74412

African (AFR) AF: 0.0980 AC: 4073 AN: 41542

American (AMR) AF: 0.189 AC: 2893 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 675 AN: 3472

East Asian (EAS) AF: 0.130 AC: 676 AN: 5190

South Asian (SAS) AF: 0.118 AC: 571 AN: 4822

European-Finnish (FIN) AF: 0.132 AC: 1400 AN: 10592

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7887 AN: 67976

Other (OTH) AF: 0.153 AC: 322 AN: 2110

Alfa AF: 0.133 Hom.: 252

Bravo AF: 0.126

Asia WGS AF: 0.170 AC: 590 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Cornelia de Lange syndrome 1 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.59
PhyloP100		0.33
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: rs78827246; hg19: chr5-37001074; COSMIC: COSV56946135; COSMIC: COSV56946135;