rs1555732963

Positions:

• chr19-45553836-T-TC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_025136.4(OPA3):​c.217dupG​(p.Glu73fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPA3 NM_025136.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.77

Genes affected

OPA3 (HGNC:8142): (outer mitochondrial membrane lipid metabolism regulator OPA3) The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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 0.598 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45553836-T-TC is Pathogenic according to our data. Variant chr19-45553836-T-TC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554806.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA3	NM_025136.4	c.217dupG	p.Glu73fs	frameshift_variant	2/2	ENST00000263275.5	NP_079412.1
OPA3	XM_006723403.5	c.58dupG	p.Glu20fs	frameshift_variant	3/3		XP_006723466.1
OPA3	NM_001017989.3	c.143-24381dupG		intron_variant			NP_001017989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000263275.5	c.217dupG	p.Glu73fs	frameshift_variant	2/2	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4	c.143-24381dupG		intron_variant		1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.58dupG	p.Glu20fs	frameshift_variant	2/2	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

3-Methylglutaconic aciduria type 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 10, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2017	- -

3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This sequence change creates a premature translational stop signal (p.Glu73Glyfs*6) in the OPA3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 107 amino acid(s) of the OPA3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OPA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 554806). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the C-terminus of the OPA3 protein. Other variant(s) that disrupt this region (p.Gln139*) have been observed in individuals with OPA3-related conditions (PMID: 18985435). This suggests that this may be a clinically significant region of the protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555732963; hg19: chr19-46057094;