8-144051482-C-CG

Variant names:

• chr8-144051482-C-CG
• rs782568024
• NM_017570.5:c.3721-11dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_017570.5(OPLAH):​c.3721-11dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 265,872 control chromosomes in the GnomAD database, including 187 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (99 hom., cov: 29)
  • Exomes 𝑓: 0.088 (88 hom.)
• Consequence: OPLAH NM_017570.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23
• Publications: 0 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)

ENSG00000293498 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-144051482-C-CG is Benign according to our data. Variant chr8-144051482-C-CG is described in ClinVar as Benign. ClinVar VariationId is 1599755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

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.3721-11dupC		intron	N/A	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.3721-11dupC		intron	N/A	ENSP00000480476.1	O14841
	OPLAH	ENST00000894965.1		c.3751-11dupC		intron	N/A	ENSP00000565024.1
	OPLAH	ENST00000919620.1		c.3745-11dupC		intron	N/A	ENSP00000589679.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 3225 AN: 23052 Hom.: 98 Cov.: 29

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.0190

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.167

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.0407 AC: 1304 AN: 32016 AF XY: 0.0389

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.0692

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0215

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0884 AC: 21462 AN: 242806 Hom.: 88 Cov.: 27 AF XY: 0.0859 AC XY: 10704 AN XY: 124560

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

African (AFR) AF: 0.124 AC: 670 AN: 5400

American (AMR) AF: 0.0655 AC: 553 AN: 8438

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 151 AN: 4550

East Asian (EAS) AF: 0.0205 AC: 199 AN: 9712

South Asian (SAS) AF: 0.0592 AC: 1016 AN: 17164

European-Finnish (FIN) AF: 0.0991 AC: 988 AN: 9966

Middle Eastern (MID) AF: 0.0601 AC: 46 AN: 766

European-Non Finnish (NFE) AF: 0.0959 AC: 16855 AN: 175680

Other (OTH) AF: 0.0884 AC: 984 AN: 11130

⚠️ 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.

GnomAD4 genome AF: 0.140 AC: 3230 AN: 23066 Hom.: 99 Cov.: 29 AF XY: 0.134 AC XY: 1515 AN XY: 11300

African (AFR) AF: 0.182 AC: 903 AN: 4970

American (AMR) AF: 0.189 AC: 393 AN: 2084

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 22 AN: 512

East Asian (EAS) AF: 0.0133 AC: 12 AN: 904

South Asian (SAS) AF: 0.0617 AC: 39 AN: 632

European-Finnish (FIN) AF: 0.208 AC: 213 AN: 1022

Middle Eastern (MID) AF: 0.167 AC: 7 AN: 42

European-Non Finnish (NFE) AF: 0.129 AC: 1602 AN: 12436

Other (OTH) AF: 0.118 AC: 36 AN: 306

Alfa AF: 0.0104 Hom.: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	5-Oxoprolinase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
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: rs782568024; hg19: chr8-145106383; COSMIC: COSV104426697; COSMIC: COSV104426697;