rs1555736803

Variant names:

• chr19-45584664-C-CT
• rs1555736803
• NM_025136.4:c.100dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_025136.4(OPA3):​c.100dupA​(p.Ser34LysfsTer45) variant causes a frameshift change. 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: OPA3 NM_025136.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.43
• 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, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45584664-C-CT is Pathogenic according to our data. Variant chr19-45584664-C-CT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 557484.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	NM_025136.4	MANE Select	c.100dupA	p.Ser34LysfsTer45	frameshift	Exon 1 of 2	NP_079412.1
	OPA3	NM_001017989.3		c.100dupA	p.Ser34LysfsTer199	frameshift	Exon 1 of 2	NP_001017989.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000263275.5	TSL:1 MANE Select	c.100dupA	p.Ser34LysfsTer45	frameshift	Exon 1 of 2	ENSP00000263275.4
	OPA3	ENST00000323060.4	TSL:1	c.100dupA	p.Ser34LysfsTer199	frameshift	Exon 1 of 2	ENSP00000319817.3
	OPA3	ENST00000544371.1	TSL:2	c.-18+17430dupA		intron	N/A	ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	3-Methylglutaconic aciduria type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

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: rs1555736803; hg19: chr19-46087922;