rs773173317
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_017807.4(OSGEP):c.740G>A(p.Arg247Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R247R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
OSGEP
NM_017807.4 missense
NM_017807.4 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.36
Genes affected
OSGEP (HGNC:18028): (O-sialoglycoprotein endopeptidase) Predicted to enable N(6)-L-threonylcarbamoyladenine synthase activity and metal ion binding activity. Involved in tRNA threonylcarbamoyladenosine modification. Located in cytoplasm; nuclear speck; and plasma membrane. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 3. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-20447957-C-T is Pathogenic according to our data. Variant chr14-20447957-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 444893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-20447957-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OSGEP | NM_017807.4 | c.740G>A | p.Arg247Gln | missense_variant | 8/11 | ENST00000206542.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OSGEP | ENST00000206542.9 | c.740G>A | p.Arg247Gln | missense_variant | 8/11 | 1 | NM_017807.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251474Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135918
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461794Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 727212
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Galloway-Mowat syndrome 3 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Galloway-Mowat syndrome 3 (GAMOS; MIM#617729). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (31 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tRNA N6-adenosine threonylcarbamoyltransferase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals with GAMOS and has been proposed as a Taiwanese/Chinese founder allele (PMIDs: 28805828, 31564459, 33333793). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate in affected siblings across two families (PMIDs: 28805828, 31564459). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The p.(Arg247Gln) mutant construct failed to rescue the proliferation rate of OSGEP knockdown human podacyte cells and was only able to partially rescue growth defects in yeast lacking the yeast ortholog of OSGEP (kae1), compared to WT (PMID: 28805828). (SP) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 10, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 247 of the OSGEP protein (p.Arg247Gln). This variant is present in population databases (rs773173317, gnomAD 0.1%). This missense change has been observed in individuals with Galloway-Mowat syndrome (PMID: 28805828, 31564459). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 444893). 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 OSGEP protein function. Experimental studies have shown that this missense change affects OSGEP function (PMID: 28805828). For these reasons, this variant has been classified as Pathogenic. - |
Nephrotic syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at T245 (P = 0.1011);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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