5-37008623-G-T

Position:

• chr5-37008623-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_133433.4(NIPBL):​c.4321G>T​(p.Val1441Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.64

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 11 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.
• PP5: Variant 5-37008623-G-T is Pathogenic according to our data. Variant chr5-37008623-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 180193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37008623-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.4321G>T	p.Val1441Leu	missense_variant, splice_region_variant	20/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.4321G>T	p.Val1441Leu	missense_variant, splice_region_variant	20/47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.4321G>T	p.Val1441Leu	missense_variant, splice_region_variant	20/46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.4321G>T	p.Val1441Leu	missense_variant, splice_region_variant	20/46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 21, 2021	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Dec 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 07, 2017	For these reasons, this variant has been classified as Pathogenic. An experimental study has shown that this missense change alters RNA splicing, producing both a normal-length transcript that contains this missense change and a minor transcript that skips exon 20 and results in a frameshift (PMID: 20358602). This variant has been reported in many individuals affected with Cornelia de Lange syndrome (PMID: 24038889, 22857006, 25574841, 23254390, 24145515, 20358602). In several of these individuals, the variant arose de novo. ClinVar contains an entry for this variant (Variation ID: 180193). This variant is not present in population databases (rs727503769, ExAC no frequency). This sequence change replaces valine with leucine at codon 1441 of the NIPBL protein (p.Val1441Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.096	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.010	B;B
Vest4		0.68
MutPred		0.33		Gain of ubiquitination at K1436 (P = 0.1725);Gain of ubiquitination at K1436 (P = 0.1725);
MVP		0.98
MPC		0.93
ClinPred		0.86	D
GERP RS		4.1
Varity_R		0.35
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503769; hg19: chr5-37008725;