Genetic Variant OPLAH:p.Gly1249Ser (chr8-144051448-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_017570.5(OPLAH):c.3745G>A(p.Gly1249Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 945,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1249R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OPLAH
NM_017570.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.60

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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>A	p.Gly1249Ser	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>A	p.Gly1249Ser	missense	Exon 27 of 27	ENSP00000480476.1	O14841
OPLAH	ENST00000894965.1		c.3775G>A	p.Gly1259Ser	missense	Exon 27 of 27	ENSP00000565024.1
OPLAH	ENST00000919620.1		c.3769G>A	p.Gly1257Ser	missense	Exon 27 of 27	ENSP00000589679.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000212

AC:

AN:

945114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

461232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21914

American (AMR)

AF:

0.00

AC:

AN:

21380

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:

53750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25886

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2832

European-Non Finnish (NFE)

AF:

0.00000264

AC:

AN:

758250

Other (OTH)

AF:

0.00

AC:

AN:

34416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.34

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.5

PhyloP100

3.6

PrimateAI

Pathogenic

0.87

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.86

MutPred

0.71

Gain of glycosylation at G1249 (P = 0.0016)

MVP

0.072

ClinPred

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.49

gMVP

0.92

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.80

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over