rs73069703

Positions:

• chr3-193654898-A-G

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.2049A>G​(p.Val683Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,918 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (34 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.280

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-193654898-A-G is Benign according to our data. Variant chr3-193654898-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00737 (1122/152314) while in subpopulation AFR AF= 0.0218 (907/41578). AF 95% confidence interval is 0.0206. There are 10 homozygotes in gnomad4. There are 541 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.2049A>G	p.Val683Val	synonymous_variant	22/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.2049A>G	p.Val683Val	synonymous_variant	22/31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152196 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00445 AC: 1116 AN: 250932 Hom.: 9 AF XY: 0.00408 AC XY: 553 AN XY: 135612

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0204

Gnomad SAS exome AF: 0.00869

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00202 AC: 2959 AN: 1461604 Hom.: 34 Cov.: 31 AF XY: 0.00217 AC XY: 1578 AN XY: 727098

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00345

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.00867

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.00737 AC: 1122 AN: 152314 Hom.: 10 Cov.: 32 AF XY: 0.00726 AC XY: 541 AN XY: 74484

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00309 Hom.: 2

Bravo AF: 0.00819

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2012	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. -

Autosomal dominant optic atrophy classic form Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.0
DANN	Benign	0.68

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: rs73069703; hg19: chr3-193372687; COSMIC: COSV104418936;