rs80358380

Variant names:

• chr5-37022088-G-A
• rs80358380
• NM_133433.4:c.5366G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_133433.4(NIPBL):​c.5366G>A​(p.Arg1789Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 9.48
• Publications: 8 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 5-37022088-G-A is Pathogenic according to our data. Variant chr5-37022088-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99932.

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.5366G>A	p.Arg1789Gln	missense	Exon 28 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.5366G>A	p.Arg1789Gln	missense	Exon 28 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.5366G>A	p.Arg1789Gln	missense	Exon 28 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.5366G>A	p.Arg1789Gln	missense	Exon 28 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.5366G>A	p.Arg1789Gln	missense	Exon 28 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.5366G>A	p.Arg1789Gln	missense	Exon 28 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.91		Gain of ubiquitination at K1794 (P = 0.0435)
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.86
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs80358380; hg19: chr5-37022190; COSMIC: COSV56950421;