8-144051372-T-A

Position:

chr8-144051372-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017570.5(OPLAH):c.3821A>T(p.Glu1274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,607,974 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1274K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

OPLAH
NM_017570.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.08

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:

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004996121).

BP6

Variant 8-144051372-T-A is Benign according to our data. Variant chr8-144051372-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1169835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000388 (59/152036) while in subpopulation EAS AF= 0.0101 (52/5140). AF 95% confidence interval is 0.00792. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPLAH	NM_017570.5 link	c.3821A>T	p.Glu1274Val	missense_variant	27/27	ENST00000618853.5	NP_060040.1	O14841

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPLAH	ENST00000618853.5 link	c.3821A>T	p.Glu1274Val	missense_variant	27/27	1	NM_017570.5	ENSP00000480476.1		O14841

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000570

AC:

137

AN:

240230

Hom.:

AF XY:

0.000636

AC XY:

AN XY:

132084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000591

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00746

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000926

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000230

AC:

335

AN:

1455938

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

174

AN XY:

724480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000452

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00715

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.000388

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0101

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000468

ExAC

AF:

0.000590

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

5-Oxoprolinase deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 30, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.22

Eigen

Benign

0.0050

Eigen_PC

Benign

-0.077

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

M_CAP

Benign

0.050

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.70

Sift4G

Benign

0.15

Polyphen

0.98

Vest4

0.58

MutPred

0.39

Loss of solvent accessibility (P = 0.0013);

MVP

0.15

ClinPred

0.12

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.46

gMVP

0.73

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

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