chr19-45553777-C-T

Variant names:

• chr19-45553777-C-T
• rs80356524
• NM_025136.4:c.277G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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). 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 NM_025136.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.77
• Publications: 13 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: Uncertain_significance. The variant received 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 VariationId is 4240.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.277G>A	p.Gly93Ser	missense	Exon 2 of 2	NP_079412.1
	OPA3	NM_001017989.3		c.143-24321G>A		intron	N/A	NP_001017989.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000263275.5	TSL:1 MANE Select	c.277G>A	p.Gly93Ser	missense	Exon 2 of 2	ENSP00000263275.4
	OPA3	ENST00000323060.4	TSL:1	c.143-24321G>A		intron	N/A	ENSP00000319817.3
	OPA3	ENST00000544371.1	TSL:2	c.118G>A	p.Gly40Ser	missense	Exon 2 of 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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.8
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.024	D
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
Mutation Taster		=9/91	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: rs80356524; hg19: chr19-46057035;