chr16-56834768-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_014669.5(NUP93):c.1772G>T(p.Gly591Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,611,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014669.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NUP93 | NM_014669.5 | c.1772G>T | p.Gly591Val | missense_variant | 16/22 | ENST00000308159.10 | |
NUP93 | NM_001242795.2 | c.1403G>T | p.Gly468Val | missense_variant | 14/20 | ||
NUP93 | NM_001242796.2 | c.1403G>T | p.Gly468Val | missense_variant | 14/20 | ||
NUP93 | XM_005256263.4 | c.1772G>T | p.Gly591Val | missense_variant | 16/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NUP93 | ENST00000308159.10 | c.1772G>T | p.Gly591Val | missense_variant | 16/22 | 1 | NM_014669.5 | P1 | |
NUP93 | ENST00000569842.5 | c.1772G>T | p.Gly591Val | missense_variant | 16/23 | 5 | |||
NUP93 | ENST00000542526.5 | c.1403G>T | p.Gly468Val | missense_variant | 14/20 | 2 | |||
NUP93 | ENST00000564887.5 | c.1403G>T | p.Gly468Val | missense_variant | 14/20 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000124 AC: 31AN: 250500Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135388
GnomAD4 exome AF: 0.000147 AC: 214AN: 1459434Hom.: 0 Cov.: 30 AF XY: 0.000167 AC XY: 121AN XY: 726012
GnomAD4 genome AF: 0.000138 AC: 21AN: 152318Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74492
ClinVar
Submissions by phenotype
Nephrotic syndrome, type 12 Pathogenic:3Uncertain:1
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | May 30, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Precision Medicine Center, Zhengzhou University | Dec 01, 2023 | PM2_p,PM3,PP3 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 20, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | NUP93: PM3:Strong, PM2:Supporting, PP3, PS3:Supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2021 | Published functional studies demonstrate a damaging effect; this variant fails to interact and reduces translocation of SMAD4 (Braun et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function and splicing; This variant is associated with the following publications: (PMID: 31517150, 30577294, 26878725, 33578576, 29869118, 33532864) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 591 of the NUP93 protein (p.Gly591Val). This variant is present in population databases (rs145473779, gnomAD 0.03%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 26878725). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NUP93 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NUP93 function (PMID: 26878725). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at