rs7624750

Positions:

chr3-193617202-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130837.3(OPA1):c.473G>A(p.Ser158Asn) variant causes a missense change. The variant allele was found at a frequency of 0.471 in 1,604,536 control chromosomes in the GnomAD database, including 180,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19086 hom., cov: 33)

Exomes 𝑓: 0.47 ( 161018 hom. )

Consequence

OPA1
NM_130837.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.4299493E-4).

BP6

Variant 3-193617202-G-A is Benign according to our data. Variant chr3-193617202-G-A is described in ClinVar as [Benign]. Clinvar id is 95727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193617202-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.473G>A	p.Ser158Asn	missense_variant	4/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.473G>A	p.Ser158Asn	missense_variant	4/31	5	NM_130837.3	ENSP00000355324	A1	O60313-10

Frequencies

GnomAD3 genomes

AF:

0.496

AC:

75338

AN:

151890

Hom.:

19057

Cov.:

show subpopulations

Gnomad AFR

AF:

0.565

Gnomad AMI

AF:

0.568

Gnomad AMR

AF:

0.444

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.397

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.573

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.468

Gnomad OTH

AF:

0.472

GnomAD3 exomes

AF:

0.467

AC:

117207

AN:

250714

Hom.:

28013

AF XY:

0.464

AC XY:

62851

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.569

Gnomad AMR exome

AF:

0.420

Gnomad ASJ exome

AF:

0.468

Gnomad EAS exome

AF:

0.395

Gnomad SAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.578

Gnomad NFE exome

AF:

0.467

Gnomad OTH exome

AF:

0.457

GnomAD4 exome

AF:

0.468

AC:

680279

AN:

1452528

Hom.:

161018

Cov.:

AF XY:

0.467

AC XY:

337540

AN XY:

723230

show subpopulations

Gnomad4 AFR exome

AF:

0.577

Gnomad4 AMR exome

AF:

0.422

Gnomad4 ASJ exome

AF:

0.475

Gnomad4 EAS exome

AF:

0.357

Gnomad4 SAS exome

AF:

0.438

Gnomad4 FIN exome

AF:

0.572

Gnomad4 NFE exome

AF:

0.468

Gnomad4 OTH exome

AF:

0.469

GnomAD4 genome

AF:

0.496

AC:

75418

AN:

152008

Hom.:

19086

Cov.:

AF XY:

0.496

AC XY:

36867

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.566

Gnomad4 AMR

AF:

0.443

Gnomad4 ASJ

AF:

0.462

Gnomad4 EAS

AF:

0.397

Gnomad4 SAS

AF:

0.426

Gnomad4 FIN

AF:

0.573

Gnomad4 NFE

AF:

0.468

Gnomad4 OTH

AF:

0.473

Alfa

AF:

0.467

Hom.:

41098

Bravo

AF:

0.491

TwinsUK

AF:

0.463

AC:

1717

ALSPAC

AF:

0.469

AC:

1807

ESP6500AA

AF:

0.562

AC:

2474

ESP6500EA

AF:

0.464

AC:

3988

ExAC

AF:

0.468

AC:

56814

Asia WGS

AF:

0.426

AC:

1480

AN:

3478

EpiCase

AF:

0.453

EpiControl

AF:

0.450

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal dominant optic atrophy classic form

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.031

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.21

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

MetaRNN

Benign

0.00034

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.32

N;N;N;N;N;.;.;N;.

REVEL

Benign

0.21

Sift

Benign

0.64

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

Sift4G

Benign

0.38

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

Polyphen

0.0

.;B;B;.;.;.;.;.;.

Vest4

0.034

MPC

0.089

ClinPred

0.015

GERP RS

3.6

Varity_R

0.031

gMVP

0.093

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