8-144054850-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_017570.5(OPLAH):c.2473G>A(p.Gly825Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00233 in 1,612,044 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

OPLAH
NM_017570.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.57

Publications

10 publications found

Variant links:

Genes affected

OPLAH (HGNC:8149): (5-oxoprolinase, ATP-hydrolysing) The protein encoded by this gene acts as a homodimer, using ATP hydrolysis to catalyze the conversion of 5-oxo-L-proline to L-glutamate. Defects in this gene are a cause of 5-oxoprolinase deficiency (OPLAHD). [provided by RefSeq, Jun 2012]

OPLAH Gene-Disease associations (from GenCC):

5-oxoprolinase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

OPLAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, REVEL [when Dann, max_spliceai, M_CAP, MetaRNN was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.1189889).

BP6

Variant 8-144054850-C-T is Benign according to our data. Variant chr8-144054850-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 578462.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00168 (255/152062) while in subpopulation AMR AF = 0.00308 (47/15272). AF 95% confidence interval is 0.00238. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017570.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPLAH	NM_017570.5	MANE Select	c.2473G>A	p.Gly825Arg	missense	Exon 18 of 27	NP_060040.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPLAH	ENST00000618853.5	TSL:1 MANE Select	c.2473G>A	p.Gly825Arg	missense	Exon 18 of 27	ENSP00000480476.1
OPLAH	ENST00000531027.1	TSL:2	n.30G>A		non_coding_transcript_exon	Exon 1 of 2
OPLAH	ENST00000527993.1	TSL:5	n.-197G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

255

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00150

AC:

367

AN:

244154

AF XY:

0.00148

show subpopulations

Gnomad AFR exome

AF:

0.000331

Gnomad AMR exome

AF:

0.00198

Gnomad ASJ exome

AF:

0.000304

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

AF:

0.00240

AC:

3507

AN:

1459982

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

1675

AN XY:

726238

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33476

American (AMR)

AF:

0.00188

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000578

AC:

AN:

51866

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00296

AC:

3286

AN:

1111762

Other (OTH)

AF:

0.00166

AC:

100

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

199

398

596

795

994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00168

AC:

255

AN:

152062

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41478

American (AMR)

AF:

0.00308

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

67982

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00179

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000702

AC:

ESP6500EA

AF:

0.00141

AC:

ExAC

AF:

0.00130

AC:

157

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00314

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

5-Oxoprolinase deficiency (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.071

MetaRNN

Benign

0.12

MetaSVM

Uncertain

-0.11

PhyloP100

5.6

PrimateAI

Uncertain

0.77

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MutPred

0.87

Gain of solvent accessibility (P = 1e-04)

MVP

0.32

ClinPred

0.082

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.93

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over