chr19-45584619-T-TCA

Variant names:

• chr19-45584619-T-TCA
• rs1555736791
• NM_025136.4:c.142+2_142+3dupTG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025136.4(OPA3):​c.142+2_142+3dupTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPA3 NM_025136.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA3	NM_025136.4	c.142+2_142+3dupTG		splice_region_variant, intron_variant	Intron 1 of 1	ENST00000263275.5	NP_079412.1
OPA3	NM_001017989.3	c.142+2_142+3dupTG		splice_region_variant, intron_variant	Intron 1 of 1		NP_001017989.2
OPA3	XM_006723403.5	c.-158+2_-158+3dupTG		splice_region_variant, intron_variant	Intron 1 of 2		XP_006723466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000263275.5	c.142+3_142+4insTG		splice_region_variant, intron_variant	Intron 1 of 1	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4	c.142+3_142+4insTG		splice_region_variant, intron_variant	Intron 1 of 1	1		ENSP00000319817.3
OPA3	ENST00000544371.1	c.-18+17475_-18+17476insTG		intron_variant	Intron 1 of 1	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the OPA3 gene. It does not directly change the encoded amino acid sequence of the OPA3 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with OPA3-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes 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, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555736791; hg19: chr19-46087877;