19-45553819-G-C

Variant names:

• chr19-45553819-G-C
• rs886037828
• NM_025136.4:c.235C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_025136.4(OPA3):​c.235C>G​(p.Leu79Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L79M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPA3 NM_025136.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.27
• Publications: 2 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45553819-G-C is Pathogenic according to our data. Variant chr19-45553819-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 225178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA3	NM_025136.4	c.235C>G	p.Leu79Val	missense_variant	Exon 2 of 2	ENST00000263275.5	NP_079412.1
OPA3	XM_006723403.5	c.76C>G	p.Leu26Val	missense_variant	Exon 3 of 3		XP_006723466.1
OPA3	NM_001017989.3	c.143-24363C>G		intron_variant	Intron 1 of 1		NP_001017989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000263275.5	c.235C>G	p.Leu79Val	missense_variant	Exon 2 of 2	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4	c.143-24363C>G		intron_variant	Intron 1 of 1	1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.76C>G	p.Leu26Val	missense_variant	Exon 2 of 2	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Optic atrophy 3 Pathogenic:1

Mar 27, 2016

Centre for Molecular Medicine and Therapeutics, University of British Columbia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		3.3
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.47
ClinPred		0.97	D
GERP RS		3.7
Varity_R		0.84
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886037828; hg19: chr19-46057077;