3-193667258-C-T

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.2961C>T(p.Arg987=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,586,394 control chromosomes in the GnomAD database, including 42 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 (32 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.111

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-193667258-C-T is Benign according to our data. Variant chr3-193667258-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00742 (1130/152240) while in subpopulation AFR AF= 0.022 (912/41540). AF 95% confidence interval is 0.0208. There are 10 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.2961C>T	p.Arg987=	synonymous_variant	29/31	ENST00000361510.8
LOC102724808	XR_924835.3	n.420+1662G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.2961C>T	p.Arg987=	synonymous_variant	29/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1128 AN: 152122 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00447 AC: 1125 AN: 251468 Hom.: 9 AF XY: 0.00411 AC XY: 559 AN XY: 135910

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0204

Gnomad SAS exome AF: 0.00879

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00202 AC: 2900 AN: 1434154 Hom.: 32 Cov.: 25 AF XY: 0.00218 AC XY: 1558 AN XY: 715520

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00343

Gnomad4 EAS exome AF: 0.0222

Gnomad4 SAS exome AF: 0.00867

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00389

GnomAD4 genome AF: 0.00742 AC: 1130 AN: 152240 Hom.: 10 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74454

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.00872

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00399 Hom.: 3

Bravo AF: 0.00824

Asia WGS AF: 0.0220 AC: 78 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2013	- -

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	-0.28
Cadd	Benign	4.6
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35540805; hg19: chr3-193385047; COSMIC: COSV104418941;