5-37008623-G-T

Variant names:

• chr5-37008623-G-T
• rs727503769
• NM_133433.4:c.4321G>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 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.
• 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 rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.4321G>T	p.Val1441Leu	missense_variant, splice_region_variant	Exon 20 of 47	ENST00000282516.13	NP_597677.2

Ensembl

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 21, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 18, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;