rs587784036

Positions:

• chr5-37052471-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_133433.4(NIPBL):​c.7168G>A​(p.Ala2390Thr) 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 Likely 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:11
• Conservation: PhyloP100: 9.45

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NIPBL. . Gene score misZ 5.5737 (greater than the threshold 3.09). Trascript score misZ 6.6817 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 5-37052471-G-A is Pathogenic according to our data. Variant chr5-37052471-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37052471-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.7168G>A	p.Ala2390Thr	missense_variant	42/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.7168G>A	p.Ala2390Thr	missense_variant	42/47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.7168G>A	p.Ala2390Thr	missense_variant	42/46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.7168G>A	p.Ala2390Thr	missense_variant	42/46			ENSP00000499536.1
NIPBL	ENST00000514335.1	n.1050G>A		non_coding_transcript_exon_variant	2/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 28, 2018	A heterozygous missense variant, NM_133433.3(NIPBL):c.7168G>A, has been identified in exon 42 of 47 of the NIPBL gene. The variant is predicted to result in a minor amino acid change from alanine to threonine at position 2390 of the protein (NP_597677.2(NIPBL):p.(Ala2390Thr)). The alanine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Nipped-B_C domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), but has previously been reported in patients with Cornelia de Lange syndrome (ClinVar, Gills L. et al. (2004), Huisman S. et al. (2013)). Analysis of parental samples indicated this variant is de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 159223). This missense change has been observed in individual(s) with classical Cornelia de Lange syndrome and mild Cornelia de Lange syndrome (PMID: 15318302, 23505322; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2390 of the NIPBL protein (p.Ala2390Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 27, 2018	A heterozygous missense variation in exon 42 of the NIPBL gene that results in the amino acid substitution of Threonine for Alanine at codon 2390 was detected. The observed variant c.7168G>A (p.Ala2390Thr) has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species Segregation analysis showed the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 14, 2022	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2022	Published functional studies demonstrate a damaging effect with impaired ATPase and DNA loop extrusion activities of cohesin (Panarotto et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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, 35476527, 23505322, 32573669, 34326454) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2017

The p.A2390T variant (also known as c.7168G>A), located in coding exon 41 of the NIPBL gene, results from a G to A substitution at nucleotide position 7168. The alanine at codon 2390 is replaced by threonine, an amino acid with similar properties. This variant was identified in 2 individuals with Cornelia de Lange syndrome. In one individual, this alteration occurred de novo, although paternity was not confirmed (Gillis LA et al. Am. J. Hum. Genet., 2004 Oct;75:610-23). The other individual was mosaic for this alteration; it was detected in buccal cells, but was absent in lymphocytes (Mannini L et al. Hum. Mutat., 2013 Dec;34:1589-96). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

NIPBL-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

The NIPBL c.7168G>A variant is predicted to result in the amino acid substitution p.Ala2390Thr. This variant was previously reported in individuals with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) (Table 1, patient 067P in Figure 1, Gillis et al. 2004. PubMed ID: 15318302), reported as de novo (Table S1, Mannini et al. 2013. PubMed ID: 24038889), or mosaic finding (Huisman et al. 2013. PubMed ID: 23505322). This variant was also identified in a two-day old critically ill infant presenting with intrauterine growth retardation, tetralogy of Fallot, highly arched eyebrow, smooth philtrum, micrognathia and microcephaly (Table e3, Lunke et al. 2020. PubMed ID: 32573669). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.58
Sift	Benign	0.046	D;T
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.79		Gain of phosphorylation at A2390 (P = 0.1274);Gain of phosphorylation at A2390 (P = 0.1274);
MVP		0.93
MPC		1.9
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784036; hg19: chr5-37052573; COSMIC: COSV56959286;