chr19-45553912-C-T

Variant names:

• chr19-45553912-C-T
• NM_025136.4:c.143-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025136.4(OPA3):​c.143-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPA3 NM_025136.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9862
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45553912-C-T is Pathogenic according to our data. Variant chr19-45553912-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1727235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA3	NM_025136.4	c.143-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 1	ENST00000263275.5	NP_079412.1
OPA3	NM_001017989.3	c.143-24456G>A		intron_variant	Intron 1 of 1		NP_001017989.2
OPA3	XM_006723403.5	c.-17-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 2		XP_006723466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000263275.5	c.143-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 1	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4	c.143-24456G>A		intron_variant	Intron 1 of 1	1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.-17-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 1	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1727235). Disruption of this splice site has been observed in individuals with 3-methylglutaconic aciduria (PMID: 11668429, 25201222, 26190011). This variant is not present in population databases (gnomAD no frequency). 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. -

3-Methylglutaconic aciduria type 3 Pathogenic:1

-

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
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		0.28		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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-46057170;