NM_133433.4:c.3015A>G

Variant names:

• chr5-36986195-A-G
• rs1669445
• NM_133433.4:c.3015A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_133433.4(NIPBL):​c.3015A>G​(p.Leu1005Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,608,350 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (261 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (254 hom.)
• Consequence: NIPBL NM_133433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.123
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 5-36986195-A-G is Benign according to our data. Variant chr5-36986195-A-G is described in ClinVar as Benign. ClinVar VariationId is 96339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.123 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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.3015A>G	p.Leu1005Leu	synonymous	Exon 10 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.3015A>G	p.Leu1005Leu	synonymous	Exon 10 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.3015A>G	p.Leu1005Leu	synonymous	Exon 10 of 46	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.3015A>G	p.Leu1005Leu	synonymous	Exon 10 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.3015A>G	p.Leu1005Leu	synonymous	Exon 10 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.3015A>G	p.Leu1005Leu	synonymous	Exon 10 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4946 AN: 152128 Hom.: 260 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.00860 AC: 2108 AN: 245176 AF XY: 0.00616

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000809

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00319 AC: 4648 AN: 1456104 Hom.: 254 Cov.: 32 AF XY: 0.00266 AC XY: 1925 AN XY: 724196

African (AFR) AF: 0.118 AC: 3874 AN: 32886

American (AMR) AF: 0.00627 AC: 274 AN: 43702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000223 AC: 19 AN: 85204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52896

Middle Eastern (MID) AF: 0.00298 AC: 17 AN: 5712

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1110140

Other (OTH) AF: 0.00673 AC: 404 AN: 60070

GnomAD4 genome AF: 0.0325 AC: 4954 AN: 152246 Hom.: 261 Cov.: 32 AF XY: 0.0314 AC XY: 2337 AN XY: 74436

African (AFR) AF: 0.113 AC: 4678 AN: 41528

American (AMR) AF: 0.0137 AC: 209 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.0237 AC: 50 AN: 2110

Alfa AF: 0.0119 Hom.: 44

Bravo AF: 0.0380

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Cornelia de Lange syndrome 1 (5)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.70
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1669445; hg19: chr5-36986297;