5-37044702-G-T

Variant names:

• chr5-37044702-G-T
• rs587784004
• NM_133433.4:c.6316G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3 PP5

The NM_133433.4(NIPBL):​c.6316G>T​(p.Val2106Leu) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.60
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_133433.4 (NIPBL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774
• PP5: Variant 5-37044702-G-T is Pathogenic according to our data. Variant chr5-37044702-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1752815. Variant chr5-37044702-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1752815. Variant chr5-37044702-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1752815. Variant chr5-37044702-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1752815. Variant chr5-37044702-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1752815. Variant chr5-37044702-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1752815.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6316G>T	p.Val2106Leu	missense_variant	Exon 36 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6316G>T	p.Val2106Leu	missense_variant	Exon 36 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6316G>T	p.Val2106Leu	missense_variant	Exon 36 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6316G>T	p.Val2106Leu	missense_variant	Exon 36 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 30, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V2106L variant (also known as c.6316G>T), located in coding exon 35 of the NIPBL gene, results from a G to T substitution at nucleotide position 6316. The valine at codon 2106 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in one individual with a diagnosis of Cornelia de Lange syndrome (CdLS) (Ambry Internal Data). Another variant at this nucleotide position (c.6316G>C), resulting in the same amino acid change, is reported in additional individuals with CdLS. In one of these individuals, this alteration occurred de novo (Latorre-Pellicer A et al. Int J Mol Sci, 2020 Feb;21:). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

NIPBL-related disorder Pathogenic:1

Aug 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NIPBL c.6316G>T variant is predicted to result in the amino acid substitution p.Val2106Leu. This variant has been previously reported in individuals with Cornelia de Lange syndrome (Figure 1A, Ansari et al. 2014. PubMed ID: 25125236; reported as de novo in Latorre-Pellicer et al. 2020. PubMed ID: 32033219). 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. -

Cornelia de Lange syndrome 1 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.V2106L in NIPBL (NM_133433.4) has been previously submitted to the ClinVar database as Likely Pathogenic but no details are available for independent assessment. The p.V2106L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has not been reported previously in affected patients to the best of our knowledge. The p.V2106L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 2106 of NIPBL is conserved in all mammalian species. The nucleotide c.6316 in NIPBL is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided Uncertain:1

Dec 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25125236, 32033219) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.80
Sift	Benign	0.36	T;T
Sift4G	Uncertain	0.017	D;D
Polyphen		0.89	P;P
Vest4		0.87
MutPred		0.23		Loss of ubiquitination at K2104 (P = 0.1079);Loss of ubiquitination at K2104 (P = 0.1079);
MVP		0.88
MPC		1.7
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.81
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587784004; hg19: chr5-37044804;