NM_130837.3:c.1773A>C

Variant names:

• chr3-193647083-A-C
• rs78767626
• NM_130837.3:c.1773A>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_130837.3(OPA1):​c.1773A>C​(p.Ala591Ala) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0670

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 3-193647083-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. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 70 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1773A>C	p.Ala591Ala	synonymous_variant	Exon 19 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1773A>C	p.Ala591Ala	synonymous_variant	Exon 19 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4741 AN: 152142 Hom.: 69 Cov.: 32

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

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.: 30 AF XY: 0.0287 AC XY: 20830 AN XY: 725988

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.: 70 Cov.: 32 AF XY: 0.0308 AC XY: 2296 AN XY: 74440

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.: 36

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 06, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
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

Other links and lift over

dbSNP: rs78767626; hg19: chr3-193364872; COSMIC: COSV104418916; COSMIC: COSV104418916;