chr3-193657175-T-C

Variant names:

• chr3-193657175-T-C
• rs9851685
• NM_130837.3:c.2274T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_130837.3(OPA1):​c.2274T>C​(p.Ala758Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,612,978 control chromosomes in the GnomAD database, including 180,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19036 hom., cov: 32)
  • Exomes 𝑓: 0.47 (161494 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.324

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]

LOC102724808 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-193657175-T-C is Benign according to our data. Variant chr3-193657175-T-C is described in ClinVar as [Benign]. Clinvar id is 95717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193657175-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.324 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.2274T>C	p.Ala758Ala	synonymous_variant	Exon 23 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.2274T>C	p.Ala758Ala	synonymous_variant	Exon 23 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75117 AN: 151774 Hom.: 19008 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.472

GnomAD3 exomes AF: 0.467 AC: 117241 AN: 251170 Hom.: 27988 AF XY: 0.463 AC XY: 62829 AN XY: 135756

Gnomad AFR exome AF: 0.569

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.384

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.468 AC: 684175 AN: 1461084 Hom.: 161494 Cov.: 37 AF XY: 0.467 AC XY: 339085 AN XY: 726830

Gnomad4 AFR exome AF: 0.576

Gnomad4 AMR exome AF: 0.422

Gnomad4 ASJ exome AF: 0.482

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.570

Gnomad4 NFE exome AF: 0.469

Gnomad4 OTH exome AF: 0.469

GnomAD4 genome AF: 0.495 AC: 75199 AN: 151894 Hom.: 19036 Cov.: 32 AF XY: 0.495 AC XY: 36754 AN XY: 74230

Gnomad4 AFR AF: 0.564

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.468

Gnomad4 OTH AF: 0.473

Alfa AF: 0.480 Hom.: 10575

Bravo AF: 0.490

Asia WGS AF: 0.420 AC: 1461 AN: 3478

EpiCase AF: 0.453

EpiControl AF: 0.450

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 30, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 23, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant optic atrophy classic form Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abortive cerebellar ataxia Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.5
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs9851685; hg19: chr3-193374964; COSMIC: COSV62479063;