3-193593399-G-T

Variant summary

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

The NM_130837.3(OPA1):c.22G>T(p.Ala8Ser) variant causes a missense 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.663

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]

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/exons	MANE	UniProt
OPA1	NM_130837.3	c.22G>T	p.Ala8Ser	missense_variant	1/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.22G>T	p.Ala8Ser	missense_variant	1/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395034 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 687894

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 8 of the OPA1 protein (p.Ala8Ser). This missense change has been observed in individual(s) with optic atrophy (PMID: 16617242). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OPA1 protein function. ClinVar contains an entry for this variant (Variation ID: 193386). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2014	p.Ala8Ser (GCT>TCT): c.22 G>T in exon 1 of the OPA1 gene (NM_015560.2). The A8S variant of unknown significance has been published as a mutation in a patient with ADOA who also had a family history of optic atrophy; however, the authors do not state whether or not other family members were tested for A8S (Han et al., 2006). A8S has not been reported as a benign polymorphism to our knowledge, and the A8S variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A8S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -

Autosomal dominant optic atrophy classic form Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 31, 2018

This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Optic atrophy 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;T;T;.;T;.;.;.
Eigen	Benign	-0.041
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.52	T;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	0.87	N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.13	N;N;N;N;N;N;N;.;N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.019	D;D;D;D;D;D;D;.;D;.
Sift4G	Benign	0.59	T;T;T;T;T;T;T;.;T;.
Polyphen		0.0010	B;.;.;P;P;.;.;.;.;.
Vest4		0.41
MutPred		0.60		Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);Gain of disorder (P = 0.0429);
MVP		0.96
MPC		0.088
ClinPred		0.64	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.091
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs794726939; hg19: chr3-193311188;