19-45553741-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_025136.4(OPA3):​c.313C>G​(p.Gln105Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q105K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OPA3 NM_025136.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O: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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795
• PP5: Variant 19-45553741-G-C is Pathogenic according to our data. 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	NM_025136.4	MANE Select	c.313C>G	p.Gln105Glu	missense	Exon 2 of 2	NP_079412.1
	OPA3	NM_001017989.3		c.143-24285C>G		intron	N/A	NP_001017989.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000263275.5	TSL:1 MANE Select	c.313C>G	p.Gln105Glu	missense	Exon 2 of 2	ENSP00000263275.4
	OPA3	ENST00000323060.4	TSL:1	c.143-24285C>G		intron	N/A	ENSP00000319817.3
	OPA3	ENST00000544371.1	TSL:2	c.154C>G	p.Gln52Glu	missense	Exon 2 of 2	ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459192 Hom.: 0 Cov.: 62 AF XY: 0.00 AC XY: 0 AN XY: 726012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111680

Other (OTH) AF: 0.00 AC: 0 AN: 60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Optic atrophy 3 (4)
2	-	-	not provided (2)
1	-	-	3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.0069
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.49
Sift	Benign	0.16	T
Sift4G	Benign	0.69	T
Polyphen		0.32	B
Vest4		0.36
MutPred		0.74		Loss of MoRF binding (P = 0.0769)
MVP		0.77
ClinPred		0.39	T
GERP RS		3.7
Varity_R		0.34
Mutation Taster		=18/82	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: rs80356525; hg19: chr19-46056999;