rs78767626

chr3-193647083-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_130837.3(OPA1):c.1773A>C(p.Ala591=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,611,292 control chromosomes in the GnomAD database, including 780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 70 hom., cov: 32)

Exomes 𝑓: 0.029 ( 710 hom. )

Consequence

OPA1
NM_130837.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0670

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 3-193647083-A-C is Benign according to our data. Variant chr3-193647083-A-C is described in ClinVar as [Benign]. Clinvar id is 95711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193647083-A-C is described in Lovd as [Benign]. Variant chr3-193647083-A-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.067 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0312 (4754/152260) while in subpopulation AFR AF= 0.0393 (1633/41532). AF 95% confidence interval is 0.0377. There are 70 homozygotes in gnomad4. There are 2296 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 69 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.1773A>C	p.Ala591=	synonymous_variant	19/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.1773A>C	p.Ala591=	synonymous_variant	19/31	5	NM_130837.3	A1	O60313-10

Frequencies

GnomAD3 genomes

AF:

0.0312

AC:

4741

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0392

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.0293

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.0285

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0299

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0256

AC:

6400

AN:

249756

Hom.:

105

AF XY:

0.0262

AC XY:

3535

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.0380

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.0367

Gnomad EAS exome

AF:

0.0252

Gnomad SAS exome

AF:

0.0252

Gnomad FIN exome

AF:

0.0294

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0286

AC:

41727

AN:

1459032

Hom.:

710

Cov.:

AF XY:

0.0287

AC XY:

20830

AN XY:

725988

show subpopulations

Gnomad4 AFR exome

AF:

0.0393

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0365

Gnomad4 EAS exome

AF:

0.0257

Gnomad4 SAS exome

AF:

0.0264

Gnomad4 FIN exome

AF:

0.0263

Gnomad4 NFE exome

AF:

0.0291

Gnomad4 OTH exome

AF:

0.0305

GnomAD4 genome

AF:

0.0312

AC:

4754

AN:

152260

Hom.:

Cov.:

AF XY:

0.0308

AC XY:

2296

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0393

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.0294

Gnomad4 SAS

AF:

0.0257

Gnomad4 FIN

AF:

0.0285

Gnomad4 NFE

AF:

0.0299

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0311

Hom.:

Bravo

AF:

0.0296

Asia WGS

AF:

0.0330

AC:

114

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0209

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

African/African American population allele frequency is 3.549% (rs78767626, 951/24904 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

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

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Benign

0.60

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