rs80356524

Positions:

• chr19-45553777-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000263275.5(OPA3):​c.277G>A​(p.Gly93Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G93G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPA3 ENST00000263275.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O: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.

• PM1: In a chain Optic atrophy 3 protein (size 177) in uniprot entity OPA3_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in ENST00000263275.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 19-45553777-C-T is Pathogenic according to our data. Variant chr19-45553777-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4240.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA3	NM_025136.4	c.277G>A	p.Gly93Ser	missense_variant	2/2	ENST00000263275.5	NP_079412.1
OPA3	XM_006723403.5	c.118G>A	p.Gly40Ser	missense_variant	3/3		XP_006723466.1
OPA3	NM_001017989.3	c.143-24321G>A		intron_variant			NP_001017989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000263275.5	c.277G>A	p.Gly93Ser	missense_variant	2/2	1	NM_025136.4	ENSP00000263275	P1
OPA3	ENST00000323060.4	c.143-24321G>A		intron_variant		1		ENSP00000319817
OPA3	ENST00000544371.1	c.118G>A	p.Gly40Ser	missense_variant	2/2	2		ENSP00000442839

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Optic atrophy 3 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	A;A;A
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.024	D;T
Polyphen		0.89	P;.
Vest4		0.75
MutPred		0.84		Gain of glycosylation at G93 (P = 0.0265);.;
MVP		0.86
ClinPred		0.90	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37

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: rs80356524; hg19: chr19-46057035;