rs794727405

Positions:

• chr3-193664952-C-T

Variant summary

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

The NM_130837.3(OPA1):​c.2734C>T​(p.Arg912Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,126 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OPA1 NM_130837.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.15

Genes affected

OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

LOC102724808 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-193664952-C-T is Pathogenic according to our data. Variant chr3-193664952-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193664952-C-T is described in Lovd as [Pathogenic]. Variant chr3-193664952-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.2734C>T	p.Arg912Ter	stop_gained	27/31	ENST00000361510.8
LOC102724808	XR_924835.3	n.420+3968G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.2734C>T	p.Arg912Ter	stop_gained	27/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456126 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724720

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2023	This sequence change creates a premature translational stop signal (p.Arg857*) in the OPA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the OPA1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with dominant optic atrophy (PMID: 28926202, 34242285). ClinVar contains an entry for this variant (Variation ID: 195896). This variant disrupts a region of the OPA1 protein in which other variant(s) (p.Val903Glyfs*3) have been determined to be pathogenic (PMID: 11017079, 26385429). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	Observed in the heterozygous state in individuals with optic atrophy in the published literature (Rocca et al., 2015; Santarelli et al., 2015); Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 19319978, 28926202, 25794858, 25564500) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2021	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.91
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs794727405; hg19: chr3-193382741; COSMIC: COSV100655295; COSMIC: COSV100655295;