14-20447275-G-A

Position:

chr14-20447275-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The NM_017807.4(OSGEP):c.973C>T(p.Arg325Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,613,912 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

OSGEP
NM_017807.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 4.18

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:

OSGEP (HGNC:):

OSGEP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-20447274-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

PP5

Variant 14-20447275-G-A is Pathogenic according to our data. Variant chr14-20447275-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449687.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr14-20447275-G-A 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.973C>T	p.Arg325Trp	missense_variant	11/11	ENST00000206542.9	NP_060277.1	Q9NPF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGEP	ENST00000206542.9 linkuse as main transcript	c.973C>T	p.Arg325Trp	missense_variant	11/11	1	NM_017807.4	ENSP00000206542.4		Q9NPF4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251470

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000213

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2017	The R325W variant in the OSGEP gene has been reported previously, in trans with the K78E variant in this patient (Braun et al., 2017). In addition, another variant at the same residue, R325Q, has been reported, either in the homozygous state or in trans with a second OSGEP variant, in multiple individuals with clinical features of Galloway-Mowat syndrome (Braun et al., 2017; Edvardson et al., 2017). The R325W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, the R325W substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R325W as a likely pathogenic variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 325 of the OSGEP protein (p.Arg325Trp). This variant is present in population databases (rs761839638, gnomAD 0.07%). This missense change has been observed in individual(s) with Galloway-Mowat syndrome (PMID: 28805828). ClinVar contains an entry for this variant (Variation ID: 449687). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects OSGEP function (PMID: 28805828). This variant disrupts the p.Arg325 amino acid residue in OSGEP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28272532, 30141175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2018

- -

Galloway-Mowat syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 20, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MVP

0.88

MPC

0.84

ClinPred

1.0

GERP RS

4.8

Varity_R

0.85

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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