NM_133433.4:c.6182C>A

Variant names:

• chr5-37044420-C-A
• rs587783999
• NM_133433.4:c.6182C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_133433.4(NIPBL):​c.6182C>A​(p.Pro2061Gln) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2061L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_133433.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

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.6182C>A	p.Pro2061Gln	missense	Exon 35 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.6182C>A	p.Pro2061Gln	missense	Exon 35 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.6182C>A	p.Pro2061Gln	missense	Exon 35 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.6182C>A	p.Pro2061Gln	missense	Exon 35 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.6182C>A	p.Pro2061Gln	missense	Exon 35 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.6182C>A	p.Pro2061Gln	missense	Exon 35 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cornelia de Lange syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.39		Gain of catalytic residue at P2061 (P = 0.0067)
MVP		0.90
MPC		2.0
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.75
gMVP		0.90
Mutation Taster		=49/51	disease causing

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: rs587783999; hg19: chr5-37044522;