Genetic Variant NM_017570.5:c.3745G>C (chr8-144051448-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_017570.5(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
NM_017570.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

Publications

1 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 links:

ENSG00000293498 (HGNC:):

ENSG00000293498 links:

SMPD5 (HGNC:52275): (sphingomyelin phosphodiesterase 5 (pseudogene)) Predicted to enable sphingomyelin phosphodiesterase activity. Predicted to be involved in ceramide biosynthetic process and sphingomyelin catabolic process. Predicted to act upstream of or within ceramide metabolic process. Predicted to be located in endoplasmic reticulum membrane and mitochondrial membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMPD5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPLAH	NM_017570.5	MANE Select	c.3745G>C	p.Gly1249Arg	missense	Exon 27 of 27	NP_060040.1	O14841

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPLAH	ENST00000618853.5	TSL:1 MANE Select	c.3745G>C	p.Gly1249Arg	missense	Exon 27 of 27	ENSP00000480476.1	O14841
OPLAH	ENST00000894965.1		c.3775G>C	p.Gly1259Arg	missense	Exon 27 of 27	ENSP00000565024.1
OPLAH	ENST00000919620.1		c.3769G>C	p.Gly1257Arg	missense	Exon 27 of 27	ENSP00000589679.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000618

AC:

AN:

161744

AF XY:

0.0000109

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 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

African (AFR)

AF:

0.00

AC:

AN:

21914

American (AMR)

AF:

0.00

AC:

AN:

21378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12368

East Asian (EAS)

AF:

0.00

AC:

AN:

14318

South Asian (SAS)

AF:

0.00

AC:

AN:

53748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25886

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2832

European-Non Finnish (NFE)

AF:

0.00000396

AC:

AN:

758250

Other (OTH)

AF:

0.00

AC:

AN:

34416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000854

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

5-Oxoprolinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

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

PhyloP100

3.6

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

Mutation Taster

=37/63

disease causing

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over