8-144051397-G-GCGACACCGGCGGTGGGGCGGGGT

Position:

• chr8-144051397-G-GCGACACCGGCGGTGGGGCGGGGT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000618853.5(OPLAH):​c.3795_3796insACCCCGCCCCACCGCCGGTGTCG​(p.Pro1266ThrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPLAH ENST00000618853.5 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -1.15

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0186 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-144051397-G-GCGACACCGGCGGTGGGGCGGGGT is Pathogenic according to our data. Variant chr8-144051397-G-GCGACACCGGCGGTGGGGCGGGGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3355213.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPLAH	NM_017570.5	c.3795_3796insACCCCGCCCCACCGCCGGTGTCG	p.Pro1266ThrfsTer40	frameshift_variant	27/27	ENST00000618853.5	NP_060040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPLAH	ENST00000618853.5	c.3795_3796insACCCCGCCCCACCGCCGGTGTCG	p.Pro1266ThrfsTer40	frameshift_variant	27/27	1	NM_017570.5	ENSP00000480476	P1
	ENST00000528912.1	n.1269_1270insACCGGCGGTGGGGCGGGGTCGAC		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

OPLAH-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The OPLAH c.3795_3796insACCCCGCCCCACCGCCGGTGTCG variant is predicted to result in a frameshift and premature protein termination (p.Pro1266Thrfs*40). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Frameshift variants in OPLAH are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-145106298;