rs186192116

Variant names:

• chr8-144053037-G-A
• rs186192116
• NM_017570.5:c.2964C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017570.5(OPLAH):​c.2964C>T​(p.Asp988Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,603,344 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: OPLAH NM_017570.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.77
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-144053037-G-A is Benign according to our data. Variant chr8-144053037-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00148 (226/152268) while in subpopulation SAS AF = 0.00477 (23/4826). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.2964C>T	p.Asp988Asp	synonymous	Exon 21 of 27	NP_060040.1	O14841

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPLAH	ENST00000618853.5	TSL:1 MANE Select	c.2964C>T	p.Asp988Asp	synonymous	Exon 21 of 27	ENSP00000480476.1	O14841
	OPLAH	ENST00000894965.1		c.2964C>T	p.Asp988Asp	synonymous	Exon 21 of 27	ENSP00000565024.1
	OPLAH	ENST00000919620.1		c.2988C>T	p.Asp996Asp	synonymous	Exon 21 of 27	ENSP00000589679.1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00247 AC: 557 AN: 225286 AF XY: 0.00287

Gnomad AFR exome AF: 0.0000774

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.000425

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00184

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00241 AC: 3503 AN: 1451076 Hom.: 9 Cov.: 35 AF XY: 0.00263 AC XY: 1899 AN XY: 721120

African (AFR) AF: 0.000180 AC: 6 AN: 33242

American (AMR) AF: 0.000371 AC: 16 AN: 43130

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 7 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39196

South Asian (SAS) AF: 0.00709 AC: 600 AN: 84636

European-Finnish (FIN) AF: 0.00183 AC: 94 AN: 51236

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5748

European-Non Finnish (NFE) AF: 0.00239 AC: 2644 AN: 1108104

Other (OTH) AF: 0.00210 AC: 126 AN: 59976

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74444

African (AFR) AF: 0.000361 AC: 15 AN: 41566

American (AMR) AF: 0.000784 AC: 12 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4826

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00241 AC: 164 AN: 67990

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00137

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	5-Oxoprolinase deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.9
DANN	Benign	0.79
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs186192116; hg19: chr8-145107940;