chr3-193618887-C-T

Position:

chr3-193618887-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_130837.3(OPA1):c.629C>T(p.Ala210Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,612,898 control chromosomes in the GnomAD database, including 696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 49 hom., cov: 33)

Exomes 𝑓: 0.027 ( 647 hom. )

Consequence

OPA1
NM_130837.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.13

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:

OPA1-AS1 (HGNC:40421): (OPA1 antisense RNA 1)

OPA1-AS1 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=0.0071130693).

BP6

Variant 3-193618887-C-T is Benign according to our data. Variant chr3-193618887-C-T is described in ClinVar as [Benign]. Clinvar id is 95729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193618887-C-T is described in Lovd as [Benign]. Variant chr3-193618887-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0237 (3613/152146) while in subpopulation NFE AF= 0.0298 (2024/68008). AF 95% confidence interval is 0.0287. There are 49 homozygotes in gnomad4. There are 1731 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 49 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.629C>T	p.Ala210Val	missense_variant	6/31	ENST00000361510.8	NP_570850.2
OPA1-AS1	NR_046634.1 linkuse as main transcript	n.214G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.629C>T	p.Ala210Val	missense_variant	6/31	5	NM_130837.3	ENSP00000355324	A1	O60313-10
OPA1-AS1	ENST00000444085.1 linkuse as main transcript	n.133G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3611

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.0374

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.0295

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0287

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0227

AC:

5716

AN:

251380

Hom.:

AF XY:

0.0233

AC XY:

3159

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.0252

Gnomad SAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.0217

GnomAD4 exome

AF:

0.0272

AC:

39755

AN:

1460752

Hom.:

647

Cov.:

AF XY:

0.0271

AC XY:

19659

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.0149

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.0367

Gnomad4 EAS exome

AF:

0.0256

Gnomad4 SAS exome

AF:

0.0163

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.0290

Gnomad4 OTH exome

AF:

0.0275

GnomAD4 genome

AF:

0.0237

AC:

3613

AN:

152146

Hom.:

Cov.:

AF XY:

0.0233

AC XY:

1731

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0149

Gnomad4 AMR

AF:

0.0162

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.0296

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.0287

Gnomad4 NFE

AF:

0.0298

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0271

Hom.:

102

Bravo

AF:

0.0217

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.0184

AC:

ESP6500EA

AF:

0.0288

AC:

248

ExAC

AF:

0.0216

AC:

2626

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0260

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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. -

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -

Autosomal dominant optic atrophy classic form

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

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

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D;D;.;D;D;D;D;D;D;D

MetaRNN

Benign

0.0071

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

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

.;.;.;M;M;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.69

N;N;N;.;N;N;.;.;.;.;D;.

REVEL

Uncertain

0.38

Sift

Benign

0.17

T;T;T;.;T;D;.;.;.;.;D;.

Sift4G

Benign

0.29

T;T;T;.;T;T;.;.;.;.;D;.

Polyphen

0.91

P;.;.;P;P;.;.;.;.;.;.;.

Vest4

0.31

MPC

0.096

ClinPred

0.018

GERP RS

5.5

Varity_R

0.072

gMVP

0.47

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