Variant 8-144051448-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000618853.5(OPLAH):c.3745G>C(p.Gly1249Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000317 in 945,110 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

OPLAH
ENST00000618853.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

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 links:

(HGNC:):

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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPLAH	NM_017570.5 linkuse as main transcript	c.3745G>C	p.Gly1249Arg	missense_variant	27/27	ENST00000618853.5	NP_060040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPLAH	ENST00000618853.5 linkuse as main transcript	c.3745G>C	p.Gly1249Arg	missense_variant	27/27	1	NM_017570.5	ENSP00000480476	P1
	ENST00000528912.1 linkuse as main transcript	n.1316C>G		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000618

AC:

AN:

161744

Hom.:

AF XY:

0.0000109

AC XY:

AN XY:

92052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000317

AC:

AN:

945110

Hom.:

Cov.:

AF XY:

0.00000434

AC XY:

AN XY:

461230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000396

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000854

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

5-Oxoprolinase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2022

This variant has not been reported in the literature in individuals affected with OPLAH-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1249 of the OPLAH protein (p.Gly1249Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Benign

0.91

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.61

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

4.1

PrimateAI

Pathogenic

0.91

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.82

Gain of methylation at G1249 (P = 0.0283);

MVP

0.081

ClinPred

0.97

GERP RS

4.9

Varity_R

0.85

gMVP

0.97

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