rs149752576

chr3-193643409-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130837.3(OPA1):c.1342A>C(p.Arg448=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00415 in 1,612,042 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (83 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-193643409-A-C is Benign according to our data. Variant chr3-193643409-A-C is described in ClinVar as [Benign]. Clinvar id is 95709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193643409-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00308 (469/152350) while in subpopulation SAS AF= 0.0172 (83/4826). AF 95% confidence interval is 0.0142. There are 3 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.1342A>C	p.Arg448=	synonymous_variant	14/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.1342A>C	p.Arg448=	synonymous_variant	14/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 471 AN: 152232 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00642 AC: 1612 AN: 251112 Hom.: 23 AF XY: 0.00782 AC XY: 1062 AN XY: 135764

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0239

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00427 AC: 6226 AN: 1459692 Hom.: 83 Cov.: 30 AF XY: 0.00509 AC XY: 3695 AN XY: 726336

Gnomad4 AFR exome AF: 0.000838

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00663

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.0239

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00497

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152350 Hom.: 3 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74504

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00275 Hom.: 2

Bravo AF: 0.00320

Asia WGS AF: 0.0120 AC: 41 AN: 3474

EpiCase AF: 0.00463

EpiControl AF: 0.00486

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2014	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	-0.50
Cadd	Benign	13
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)		0.060		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: rs149752576; hg19: chr3-193361198; COSMIC: COSV100655178; COSMIC: COSV100655178;