rs1555732963

Variant names:

• chr19-45553836-T-TC
• rs1555732963
• NM_025136.4:c.217dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_025136.4(OPA3):​c.217dupG​(p.Glu73GlyfsTer6) 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
• Publications: 0 publications found

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]

OPA3 Gene-Disease associations (from GenCC):

• optic atrophy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 3-methylglutaconic aciduria type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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. There are 16 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 VariationId is 554806.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025136.4. 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
	OPA3	NM_025136.4	MANE Select	c.217dupG	p.Glu73GlyfsTer6	frameshift	Exon 2 of 2	NP_079412.1	Q9H6K4-1
	OPA3	NM_001017989.3		c.143-24381dupG		intron	N/A	NP_001017989.2	Q9H6K4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000263275.5	TSL:1 MANE Select	c.217dupG	p.Glu73GlyfsTer6	frameshift	Exon 2 of 2	ENSP00000263275.4	Q9H6K4-1
	OPA3	ENST00000323060.4	TSL:1	c.143-24381dupG		intron	N/A	ENSP00000319817.3	Q9H6K4-2
	OPA3	ENST00000544371.1	TSL:2	c.58dupG	p.Glu20GlyfsTer6	frameshift	Exon 2 of 2	ENSP00000442839.1	B4DK77

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	3-Methylglutaconic aciduria type 3 (2)
-	1	-	3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=15/185	disease causing (ClinVar)

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: rs1555732963; hg19: chr19-46057094;