5-37022088-G-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_133433.4(NIPBL):c.5366G>A(p.Arg1789Gln) 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. R1789L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_133433.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.5366G>A | p.Arg1789Gln | missense_variant | 28/47 | 1 | NM_133433.4 | ENSP00000282516.8 | ||
NIPBL | ENST00000448238.2 | c.5366G>A | p.Arg1789Gln | missense_variant | 28/46 | 1 | ENSP00000406266.2 | |||
NIPBL | ENST00000652901.1 | c.5366G>A | p.Arg1789Gln | missense_variant | 28/46 | ENSP00000499536.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:4Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Uncertain significance, flagged submission | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 24, 2017 | This sequence change replaces arginine with glutamine at codon 1789 of the NIPBL protein (p.Arg1789Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant has not been reported in the literature in individuals with NIPBL-related disease. ClinVar contains an entry for this variant (Variation ID: 99932). This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 09, 2020 | This variant was identified as de novo (maternity and paternity confirmed). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NIPBL related disorder (PMID: VCV000099932.5). Different missense changes at the same codon (p.Arg1789Gly, p.Arg1789Leu) have been reported to be associated with NIPBL related disorder (PMID: 15318302, 20583156). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2024 | The c.5366G>A (p.R1789Q) alteration is located in exon 28 (coding exon 27) of the NIPBL gene. This alteration results from a G to A substitution at nucleotide position 5366, causing the arginine (R) at amino acid position 1789 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at