rs587784024

chr5-37049240-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_133433.4(NIPBL):c.6893G>A(p.Arg2298His) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2298C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-37049239-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 159210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NIPBL
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 5-37049240-G-A is Pathogenic according to our data. Variant chr5-37049240-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37049240-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.6893G>A	p.Arg2298His	missense_variant	40/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.6893G>A	p.Arg2298His	missense_variant	40/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.6893G>A	p.Arg2298His	missense_variant	40/46	1
NIPBL	ENST00000652901.1	c.6893G>A	p.Arg2298His	missense_variant	40/46

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2298 of the NIPBL protein (p.Arg2298His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg2298 amino acid residue in NIPBL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16236812). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NIPBL protein function. ClinVar contains an entry for this variant (Variation ID: 159211). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 15318302). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15318302, 17640042, 16606884, 16100726, 26725122) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 24, 2020	- -

NIPBL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2023

The NIPBL c.6893G>A variant is predicted to result in the amino acid substitution p.Arg2298His. This variant has been previously reported as de novo in two individuals with Cornelia de Lange syndrome (Gillis et al. 2004. PubMed ID: 15318302). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different amino acids substitutions at the same residue (p.Arg2298Cys, p.Arg2298Ser, and p.Arg2298Leu) have also been reported in individuals with Cornelia de Lange syndrome (Gillis et al. 2004. PubMed ID: 15318302; Bhuiyan et al. 2006. PubMed ID: 16236812; Selicorni et al. 2007. PubMed ID: 17661813; Table 4 - Jiao et al. 2019. PubMed ID: 30945278). In summary, c.6893G>A (p.Arg2298His) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.135);Gain of disorder (P = 0.135);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784024; hg19: chr5-37049342; COSMIC: COSV56950574; COSMIC: COSV56950574;