rs587784020
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PP2PP3_ModeratePP5
The NM_133433.4(NIPBL):c.6646T>C(p.Tyr2216His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2216S) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes đť‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NIPBL
NM_133433.4 missense
NM_133433.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.65
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 6 ACMG points.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr5-37048559-A-C is described in Lovd as [Pathogenic].
PP2
?
Missense variant where missense usually causes diseases, NIPBL
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
?
Variant 5-37048558-T-C is Pathogenic according to our data. Variant chr5-37048558-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159205.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.6646T>C | p.Tyr2216His | missense_variant | 39/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.6646T>C | p.Tyr2216His | missense_variant | 39/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.6646T>C | p.Tyr2216His | missense_variant | 39/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.6646T>C | p.Tyr2216His | missense_variant | 39/46 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1438070Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 714922
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1438070
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
714922
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2018 | This sequence change replaces tyrosine with histidine at codon 2216 of the NIPBL protein (p.Tyr2216His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Cornelia de Lange syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 159205). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Two other missense variants at this residue (p.Tyr2216Cys and p.Try2216Ser) in NIPBL have been determined to be clinically significant (PMID:24874887, 24635725). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of disorder (P = 0.0254);Gain of disorder (P = 0.0254);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at