rs587783935
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6
The NM_133433.4(NIPBL):c.3868G>A(p.Glu1290Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000382 in 1,569,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
NIPBL
NM_133433.4 missense
NM_133433.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 6.47
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 Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, NIPBL
BP6
?
Variant 5-37006369-G-A is Benign according to our data. Variant chr5-37006369-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159101.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.3868G>A | p.Glu1290Lys | missense_variant | 17/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.3868G>A | p.Glu1290Lys | missense_variant | 17/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.3868G>A | p.Glu1290Lys | missense_variant | 17/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.3868G>A | p.Glu1290Lys | missense_variant | 17/46 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151996Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251088Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135730
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GnomAD4 exome AF: 0.00000282 AC: 4AN: 1417372Hom.: 0 Cov.: 27 AF XY: 0.00000283 AC XY: 2AN XY: 707916
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151996Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74220
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Gain of ubiquitination at E1290 (P = 0.0082);Gain of ubiquitination at E1290 (P = 0.0082);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at