14-20447274-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_017807.4(OSGEP):c.974G>A(p.Arg325Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

OSGEP
NM_017807.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-20447275-G-A is described in Lovd as [Likely_pathogenic].

PP5

Variant 14-20447274-C-T is Pathogenic according to our data. Variant chr14-20447274-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 444886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-20447274-C-T is described in Lovd as [Pathogenic]. Variant chr14-20447274-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSGEP	NM_017807.4 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 11 of 11	ENST00000206542.9	NP_060277.1	Q9NPF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSGEP	ENST00000206542.9 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 11 of 11	1	NM_017807.4	ENSP00000206542.4		Q9NPF4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251478

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galloway-Mowat syndrome 3

Pathogenic:3

Oct 26, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OSGEP c.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the Gcp-like domain (IPR000905) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes. c.974G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Galloway-Mowat Syndrome 3 (e.g., Braun_2017, Edvardson_2017), and the variant was shown to segregate with disease in at least one family. These data indicate that the variant is very likely to be associated with disease. Additionally, multiple publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced N6-threonyl-carbamoyl-adenosine levels and increased DNA-damage response signaling (e.g., Braun_2017, Edvardson_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28805828, 28272532). ClinVar contains an entry for this variant (Variation ID: 444886). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 08, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was previously reported in multiple individuals with Galloway-Mowat syndrome 3 in homozygous state or in trans with a second OSGEP variant and segregated with the disease in family [PMID: 28272532, 28805828]. Functional studies suggested that the variant has a pathogenic effect by perturbing t6A synthesis, thereby interfering with global protein production [PMID: 28272532]. -

not provided

Pathogenic:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 325 of the OSGEP protein (p.Arg325Gln). This variant is present in population databases (rs753237335, gnomAD 0.005%). This missense change has been observed in individuals with Galloway-Mowat syndrome (PMID: 28272532, 28805828, 30141175, 31481669). ClinVar contains an entry for this variant (Variation ID: 444886). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects OSGEP function (PMID: 28272532, 28805828). For these reasons, this variant has been classified as Pathogenic. -

Galloway-Mowat syndrome

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.63

MutPred

0.43

Loss of catalytic residue at R325 (P = 0.0666);

MVP

0.84

MPC

0.58

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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