5-37044636-G-T

Variant names:

• chr5-37044636-G-T
• rs587784002
• NM_133433.4:c.6250G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_133433.4(NIPBL):​c.6250G>T​(p.Val2084Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_133433.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-37044636-G-T is Pathogenic according to our data. Variant chr5-37044636-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 159183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37044636-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 159183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37044636-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 159183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37044636-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 159183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37044636-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 159183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37044636-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 159183.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6250G>T	p.Val2084Leu	missense_variant, splice_region_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.6250G>T	p.Val2084Leu	missense_variant, splice_region_variant	Exon 36 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6250G>T	p.Val2084Leu	missense_variant, splice_region_variant	Exon 36 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6250G>T	p.Val2084Leu	missense_variant, splice_region_variant	Exon 36 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.20
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.011	D;D
Polyphen		0.43	B;P
Vest4		0.81
MutPred		0.29		Loss of methylation at K2079 (P = 0.0746);Loss of methylation at K2079 (P = 0.0746);
MVP		0.81
MPC		1.7
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.84
Mutation Taster		=51/49	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.83		Position offset: 0

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

Other links and lift over

dbSNP: rs587784002; hg19: chr5-37044738;