rs28937899

Positions:

• chr19-45553639-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_025136.4(OPA3):​c.415C>T​(p.Gln139*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000206 in 1,453,420 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OPA3 NM_025136.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.07

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.231 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45553639-G-A is Pathogenic according to our data. Variant chr19-45553639-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21710.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA3	NM_025136.4	c.415C>T	p.Gln139*	stop_gained	2/2	ENST00000263275.5	NP_079412.1
OPA3	XM_006723403.5	c.256C>T	p.Gln86*	stop_gained	3/3		XP_006723466.1
OPA3	NM_001017989.3	c.143-24183C>T		intron_variant			NP_001017989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000263275.5	c.415C>T	p.Gln139*	stop_gained	2/2	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4	c.143-24183C>T		intron_variant		1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.256C>T	p.Gln86*	stop_gained	2/2	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453420 Hom.: 0 Cov.: 62 AF XY: 0.00000277 AC XY: 2 AN XY: 723058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 3 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	Found in an individual of Indian origin with Costeff syndrome -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.83
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28937899; hg19: chr19-46056897;