19-45553741-G-T

Variant names:

• chr19-45553741-G-T
• rs80356525
• NM_025136.4:c.313C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_025136.4(OPA3):​c.313C>A​(p.Gln105Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q105E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPA3 NM_025136.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89
• Publications: 12 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-45553741-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13402954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA3	NM_025136.4	c.313C>A	p.Gln105Lys	missense_variant	Exon 2 of 2	ENST00000263275.5	NP_079412.1
OPA3	XM_006723403.5	c.154C>A	p.Gln52Lys	missense_variant	Exon 3 of 3		XP_006723466.1
OPA3	NM_001017989.3	c.143-24285C>A		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.313C>A	p.Gln105Lys	missense_variant	Exon 2 of 2	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4	c.143-24285C>A		intron_variant	Intron 1 of 1	1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.154C>A	p.Gln52Lys	missense_variant	Exon 2 of 2	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gln105 amino acid residue in OPA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15342707, 24136862, 25159689). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 105 of the OPA3 protein (p.Gln105Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OPA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1416933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.0091	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		2.9
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.0070	B;.
Vest4		0.16
MutPred		0.48		Gain of methylation at Q105 (P = 0.0126);.;
MVP		0.80
ClinPred		0.33	T
GERP RS		3.7
Varity_R		0.24
Mutation Taster		=49/51	disease causing

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: rs80356525; hg19: chr19-46056999;