rs80356523

chr19-45553912-C-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_025136.4(OPA3):c.143-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000207 in 1,450,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OPA3 NM_025136.4 splice_acceptor
• Scores: Splicing: ADA: 0.9862
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 6.77

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 Pathogenic. Variant got 19 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-45553912-C-G is Pathogenic according to our data. Variant chr19-45553912-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA3	NM_025136.4	c.143-1G>C		splice_acceptor_variant		ENST00000263275.5
OPA3	XM_006723403.5	c.-17-1G>C		splice_acceptor_variant
OPA3	NM_001017989.3	c.143-24456G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA3	ENST00000263275.5	c.143-1G>C		splice_acceptor_variant		1	NM_025136.4	P1
OPA3	ENST00000323060.4	c.143-24456G>C		intron_variant		1
OPA3	ENST00000544371.1	c.-17-1G>C		splice_acceptor_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450454 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719224

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 3 Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Accounts for 100% of pathogenic variants of individuals of Iraqi Jewish origin with Costeff syndrome -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_025136.3(OPA3):c.143-1G>C is classified as pathogenic in the context of Costeff optic atrophy syndrome. Sources cited for classification include the following: PMID 15902555, 25201222, 11668429 and 20350831. Classification of NM_025136.3(OPA3):c.143-1G>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2001	- -

3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change affects an acceptor splice site in intron 1 of the OPA3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with 3-methylglutaconic aciduria (PMID: 11668429, 25201222, 26190011). ClinVar contains an entry for this variant (Variation ID: 4239). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 13, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: -18
DS_AL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356523; hg19: chr19-46057170;