Genetic Variant OPLAH:c.3721-11delC (chr8-144051482-CG-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_017570.5(OPLAH):c.3721-11delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 263,156 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0042 ( 3 hom., cov: 29)

Exomes 𝑓: 0.017 ( 5 hom. )

Consequence

OPLAH
NM_017570.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23

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 Gene-Disease associations (from GenCC):

5-oxoprolinase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

OPLAH links:

ENSG00000293498 (HGNC:):

ENSG00000293498 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 8-144051482-CG-C is Benign according to our data. Variant chr8-144051482-CG-C is described in ClinVar as Benign. ClinVar VariationId is 2072722.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00416 (97/23326) while in subpopulation AFR AF = 0.0159 (80/5020). AF 95% confidence interval is 0.0131. There are 3 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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.3721-11delC		intron	N/A	NP_060040.1	O14841

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OPLAH	ENST00000618853.5	TSL:1 MANE Select	c.3721-11delC	intron	N/A	ENSP00000480476.1	O14841
OPLAH	ENST00000894965.1		c.3751-11delC	intron	N/A	ENSP00000565024.1
OPLAH	ENST00000919620.1		c.3745-11delC	intron	N/A	ENSP00000589679.1

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

AN:

23312

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00287

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00441

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000954

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00325

GnomAD2 exomes

AF:

0.0361

AC:

1157

AN:

32016

AF XY:

0.0371

show subpopulations

Gnomad AFR exome

AF:

0.0491

Gnomad AMR exome

AF:

0.0365

Gnomad ASJ exome

AF:

0.0377

Gnomad EAS exome

AF:

0.0384

Gnomad FIN exome

AF:

0.0384

Gnomad NFE exome

AF:

0.0344

Gnomad OTH exome

AF:

0.0391

GnomAD4 exome

AF:

0.0174

AC:

4172

AN:

239830

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

2061

AN XY:

123118

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0162

AC:

AN:

5424

American (AMR)

AF:

0.0167

AC:

140

AN:

8360

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

AN:

4572

East Asian (EAS)

AF:

0.0119

AC:

113

AN:

9494

South Asian (SAS)

AF:

0.0118

AC:

206

AN:

17520

European-Finnish (FIN)

AF:

0.00830

AC:

AN:

9994

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

768

European-Non Finnish (NFE)

AF:

0.0192

AC:

3318

AN:

172544

Other (OTH)

AF:

0.0141

AC:

157

AN:

11154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

583

1166

1748

2331

2914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<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

AF:

0.00416

AC:

AN:

23326

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

AN XY:

11408

show subpopulations

African (AFR)

AF:

0.0159

AC:

AN:

5020

American (AMR)

AF:

0.00286

AC:

AN:

2100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

522

East Asian (EAS)

AF:

0.00441

AC:

AN:

908

South Asian (SAS)

AF:

0.00

AC:

AN:

640

European-Finnish (FIN)

AF:

0.000954

AC:

AN:

1048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

12580

Other (OTH)

AF:

0.00325

AC:

AN:

308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.574

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

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

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

8-144051482-CGGGGGG-CGGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over