8-144051373-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_017570.5(OPLAH):​c.3820G>A​(p.Glu1274Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,607,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict 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. E1274V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000098 ( 1 hom. )

Consequence

OPLAH
NM_017570.5 missense

Scores

3
12

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.333
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.006231755).
BP6
Variant 8-144051373-C-T is Benign according to our data. Variant chr8-144051373-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1130802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144051373-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000198 (30/151714) while in subpopulation EAS AF= 0.0039 (20/5122). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OPLAHNM_017570.5 linkc.3820G>A p.Glu1274Lys missense_variant Exon 27 of 27 ENST00000618853.5 NP_060040.1 O14841

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OPLAHENST00000618853.5 linkc.3820G>A p.Glu1274Lys missense_variant Exon 27 of 27 1 NM_017570.5 ENSP00000480476.1 O14841

Frequencies

GnomAD3 genomes
AF:
0.000198
AC:
30
AN:
151598
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000968
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000658
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00390
Gnomad SAS
AF:
0.000830
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000221
AC:
53
AN:
239718
Hom.:
0
AF XY:
0.000205
AC XY:
27
AN XY:
131890
show subpopulations
Gnomad AFR exome
AF:
0.0000710
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00225
Gnomad SAS exome
AF:
0.000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000693
GnomAD4 exome
AF:
0.0000983
AC:
143
AN:
1455354
Hom.:
1
Cov.:
34
AF XY:
0.000127
AC XY:
92
AN XY:
724152
show subpopulations
Gnomad4 AFR exome
AF:
0.0000609
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00110
Gnomad4 SAS exome
AF:
0.000639
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000811
Gnomad4 OTH exome
AF:
0.000566
GnomAD4 genome
AF:
0.000198
AC:
30
AN:
151714
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74140
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00390
Gnomad4 SAS
AF:
0.000831
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000194
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.000270
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000266
AC:
32
Asia WGS
AF:
0.00751
AC:
26
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

5-Oxoprolinase deficiency Benign:1
Jun 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
20
DANN
Benign
0.86
DEOGEN2
Benign
0.044
T
Eigen
Benign
0.036
Eigen_PC
Benign
-0.059
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.0062
T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.7
L
PrimateAI
Uncertain
0.76
T
Sift4G
Benign
0.49
T
Polyphen
1.0
D
Vest4
0.28
MVP
0.15
ClinPred
0.10
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.15
gMVP
0.71

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.

Other links and lift over

dbSNP: rs371840526; hg19: chr8-145106274; API