chr14-20447957-C-T

Position:

chr14-20447957-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000206542.9(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
ENST00000206542.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 7.36

Variant links:

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]

OSGEP links:

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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	Protein	UniProt
OSGEP	NM_017807.4 linkuse as main transcript	c.740G>A	p.Arg247Gln	missense_variant	8/11	ENST00000206542.9	NP_060277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGEP	ENST00000206542.9 linkuse as main transcript	c.740G>A	p.Arg247Gln	missense_variant	8/11	1	NM_017807.4	ENSP00000206542	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251474

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00147

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.0000659

AC:

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, 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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 30, 2017	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

0.00090

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.84

MutPred

0.66

Loss of phosphorylation at T245 (P = 0.1011);

MVP

0.70

MPC

0.90

ClinPred

0.51

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over