Variant chr3-193593399-G-T details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.663

Variant links:

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]

OPA1 links:

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ACMG classification

Classification made for transcript

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
OPA1	NM_130837.3 link	c.22G>T	p.Ala8Ser	missense_variant	Exon 1 of 31	ENST00000361510.8	NP_570850.2	O60313-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 link	c.22G>T	p.Ala8Ser	missense_variant	Exon 1 of 31	5	NM_130837.3	ENSP00000355324.2		O60313-10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1395034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2022	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). This missense change has been observed in individual(s) with optic atrophy (PMID: 16617242). 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). -

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

BayesDel_noAF

Uncertain

0.020

CADD

Benign

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

LIST_S2

Benign

0.52

T;T;T;T;.;T;T;T;T;T

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.81

.;L;L;L;L;L;.;L;L;.

PrimateAI

Uncertain

0.51

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over