chr19-45553777-C-T

Position:

• chr19-45553777-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_025136.4(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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPA3 NM_025136.4 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 Uncertain_significance. Variant got 5 ACMG points.

• 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	ENSP00000263275.4
OPA3	ENST00000323060.4	c.143-24321G>A		intron_variant		1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.118G>A	p.Gly40Ser	missense_variant	2/2	2		ENSP00000442839.1

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

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

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;.
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;