NM_130837.3:c.321G>A

Variant names:

• chr3-193615011-G-A
• rs117888848
• NM_130837.3:c.321G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_130837.3(OPA1):​c.321G>A​(p.Ser107Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,114 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (81 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• 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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-193615011-G-A is Benign according to our data. Variant chr3-193615011-G-A is described in ClinVar as [Benign]. Clinvar id is 95724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193615011-G-A is described in Lovd as [Benign]. Variant chr3-193615011-G-A 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 sas. gnomad4 allele frequency = 0.00287 (437/152290) while in subpopulation SAS AF= 0.0166 (80/4822). AF 95% confidence interval is 0.0137. There are 3 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.321G>A	p.Ser107Ser	synonymous_variant	Exon 2 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.321G>A	p.Ser107Ser	synonymous_variant	Exon 2 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 439 AN: 152172 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00616 AC: 1532 AN: 248716 Hom.: 21 AF XY: 0.00747 AC XY: 1007 AN XY: 134738

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00409 AC: 5977 AN: 1461824 Hom.: 81 Cov.: 33 AF XY: 0.00488 AC XY: 3546 AN XY: 727216

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00654

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00314 AC XY: 234 AN XY: 74458

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00260 Hom.: 2

Bravo AF: 0.00289

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 04, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

not specified Benign:2

Apr 23, 2014

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. -

Jul 01, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant optic atrophy classic form Benign:2

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. -

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	-0.43
CADD	Benign	7.7
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs117888848; hg19: chr3-193332800; COSMIC: COSV100655177; COSMIC: COSV100655177;