rs587784035

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_133433.4(NIPBL):​c.7141G>A​(p.Gly2381Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2381A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NIPBL
NM_133433.4 missense

Scores

9
9
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
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, 0.867
PP5
Variant 5-37052444-G-A is Pathogenic according to our data. Variant chr5-37052444-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159222.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NIPBLNM_133433.4 linkc.7141G>A p.Gly2381Ser missense_variant Exon 42 of 47 ENST00000282516.13 NP_597677.2 Q6KC79-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NIPBLENST00000282516.13 linkc.7141G>A p.Gly2381Ser missense_variant Exon 42 of 47 1 NM_133433.4 ENSP00000282516.8 Q6KC79-1
NIPBLENST00000448238.2 linkc.7141G>A p.Gly2381Ser missense_variant Exon 42 of 46 1 ENSP00000406266.2 Q6KC79-2
NIPBLENST00000652901.1 linkc.7141G>A p.Gly2381Ser missense_variant Exon 42 of 46 ENSP00000499536.1 A0A590UJS4
NIPBLENST00000514335.1 linkn.1023G>A non_coding_transcript_exon_variant Exon 2 of 7 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

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
0.99
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Uncertain
2.8
M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.023
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.41
Gain of phosphorylation at G2381 (P = 0.0463);Gain of phosphorylation at G2381 (P = 0.0463);
MVP
0.94
MPC
2.1
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.78
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs587784035; hg19: chr5-37052546; API