rs587784036

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.45

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the NIPBL gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 5.5737 (above the threshold of 3.09). Trascript score misZ: 6.6817 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.7168G>A	p.Ala2390Thr	missense_variant	Exon 42 of 47	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPBL	ENST00000282516.13 link	c.7168G>A	p.Ala2390Thr	missense_variant	Exon 42 of 47	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.7168G>A	p.Ala2390Thr	missense_variant	Exon 42 of 46	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.7168G>A	p.Ala2390Thr	missense_variant	Exon 42 of 46			ENSP00000499536.1	A0A590UJS4
NIPBL	ENST00000514335.1 link	n.1050G>A		non_coding_transcript_exon_variant	Exon 2 of 7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Pathogenic:7

Apr 29, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NIPBL gene is highly constrained (Z-score= 6.68 and pLI = 1), which suggests it is intolerant to variation. The c.7168G>A (p.Ala2390Thr) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a heterozygous change in individuals with Cornelia de Lange syndrome 1, including as a de novo event (PMID: 15318302, 32573669, 37377026, 34326454). Functional studies illustrated that this variant does not stimulate cohesin's ATPase activity (PMID: 35476527). The c.7168G>A (p.Ala2390Thr) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.7168G>A (p.Ala2390Thr) is classified as Pathogenic. -

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. For these reasons, this variant has been classified as Pathogenic. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2018

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 28, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:3

May 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Apr 11, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.084

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.74

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over