rs1554030218

Variant names:

• chr5-37038663-A-T
• rs1554030218
• NM_133433.4:c.6033A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133433.4(NIPBL):​c.6033A>T​(p.Leu2011Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 2.92
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6033A>T	p.Leu2011Phe	missense_variant	Exon 34 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6033A>T	p.Leu2011Phe	missense_variant	Exon 34 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6033A>T	p.Leu2011Phe	missense_variant	Exon 34 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6033A>T	p.Leu2011Phe	missense_variant	Exon 34 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Uncertain:1

Oct 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with NIPBL-related disease. This sequence change replaces leucine with phenylalanine at codon 2011 of the NIPBL protein (p.Leu2011Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		2.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.57
MutPred		0.39		Gain of MoRF binding (P = 0.1821);Gain of MoRF binding (P = 0.1821);
MVP		0.84
MPC		2.1
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.63
gMVP		0.55
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554030218; hg19: chr5-37038765;