rs1382779104

Variant names:

• chr19-45553840-T-C
• rs1382779104
• NM_025136.4:c.214A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_025136.4(OPA3):​c.214A>G​(p.Asn72Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,716 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N72N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: OPA3 NM_025136.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.86
• Publications: 0 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, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_025136.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

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.214A>G	p.Asn72Asp	missense	Exon 2 of 2	NP_079412.1	Q9H6K4-1
	OPA3	NM_001017989.3		c.143-24384A>G		intron	N/A	NP_001017989.2	Q9H6K4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000263275.5	TSL:1 MANE Select	c.214A>G	p.Asn72Asp	missense	Exon 2 of 2	ENSP00000263275.4	Q9H6K4-1
	OPA3	ENST00000323060.4	TSL:1	c.143-24384A>G		intron	N/A	ENSP00000319817.3	Q9H6K4-2
	OPA3	ENST00000544371.1	TSL:2	c.55A>G	p.Asn19Asp	missense	Exon 2 of 2	ENSP00000442839.1	B4DK77

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246722 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460716 Hom.: 0 Cov.: 34 AF XY: 0.00000826 AC XY: 6 AN XY: 726582

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111454

Other (OTH) AF: 0.0000331 AC: 2 AN: 60356

GnomAD4 genome Cov.: 33

Alfa AF: 0.000223 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-Methylglutaconic aciduria type 3 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.9
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.81		Loss of methylation at K69 (P = 0.0827)
MVP		0.78
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.80
Mutation Taster		=45/55	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: rs1382779104; hg19: chr19-46057098;